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Lumiracoxib…Selective cyclooxygenase-2-(COX-2) inhibitor. Anti-inflammatory.

July 31, 2014 7:21 am / Leave a comment

Lumiracoxib

2-[(2-Chloro-6-fluorophenyl)amino]-5-methylbenzeneacetic Acid;

2-[2-(2-Chloro-6-fluorophenylamino)-5-methylphenyl]acetic Acid;

CGS 35189; COX 189; Prexige;

Applications: Selective cyclooxygenase-2-(COX-2) inhibitor. Anti-inflammatory.

Lumiracoxib
Systematic (IUPAC) name

{2-[(2-chloro-6-fluorophenyl)amino]-5-methylphenyl} acetic acid
Clinical data
Trade names	Prexige
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	C (AU)
Legal status	℞-only Withdrawn (Australia, New Zealand, Canada, UK, Germany,Austria, Belgium, Cyprus, Brazil)
Routes	Oral
Pharmacokinetic data
Bioavailability	74-90%^[1]
Protein binding	>98%^[1]
Metabolism	Predominantly in the liver viaoxidation and hydroxylation(CYP2C9)^[1]
Half-life	5-8 hours^[1]
Excretion	Urine (54%) and faeces (43%)^[1]
Identifiers
CAS number	220991-20-8
ATC code	M01AH06
PubChem	CID 151166
DrugBank	DB01283
ChemSpider	133236
UNII

PDB ligand ID	LUR (PDBe, RCSB PDB)
Chemical data
Formula	C₁₅H₁₃Cl F N O₂
Mol. mass	293.72 g/mol

Lumiracoxib (rINN) is a carboxylic acid COX-2 selective inhibitor non-steroidal anti-inflammatory drug, manufactured by Novartis and still sold in few countries, including Mexico, Ecuador and the Dominican Republic, under the trade name Prexige (sometimes misquoted as “Prestige” by the media).^[1]

Lumiracoxib has several distinctive features. Its structure is different from that of other COX-2 inhibitors, such as celecoxib: lumiracoxib is an analogue of diclofenac (one chlorine substituted by fluorine, the phenylacetic acid has another methyl group in meta position), making it a member of the arylalkanoic acid class of NSAIDs; it binds to a different site on the COX-2 enzyme than do other COX-2 inhibitors; it is the only acidic coxib and has the highest COX-2 selectivity of any NSAID.^[2]

Since its original approval, lumiracoxib has been withdrawn from the market in several countries, mostly due to its potential for causing liver failure (sometimes requiring liver transplantation). It has never been approved for use in the United States.^[1]

History

The TARGET study (Therapeutic Arthritis Research and Gastrointestinal Event Trial) was conducted with more than 18,000 patients to test its gastrointestinal and cardiovascular safety against naproxen and ibuprofen and also study its efficacy against these two NSAIDs.

In November 2006, Prexige received marketing approval for all European Union countries through a common procedure called MRP. However, in August 2007, Prexige was withdrawn from the market in Australia following 8 serious liver adverse events, including 2 deaths and 2 liver transplants.^[3] On September 27, 2007, the US Food and Drug Administration issued a not approvable letter for lumiracoxib, requiring additional safety data.^[4] Canada withdrew Prexige (approved at 100 mg dose only) in October 2007.^[5] Several European Union countries followed suit in November 2007.^[6]

The FDA rejected Prexige as a trade name for lumiracoxib in 2003. Prexede was suggested as an alternative, but the FDA Division of Medication Errors and Technical Support (DMETS) subsequently recommended against it as well.^[7]

Withdrawal from market

On August 11, 2007, Australia’s Therapeutic Goods Administration (TGA, the national agency responsible for regulation of pharmaceuticals) cancelled the registration of lumiracoxib in Australia due to concerns that it may cause liver failure.^[8]

According to the TGA’s Principal Medical Adviser, Dr Rohan Hammett, as of 10 August 2007 the TGA had received 8 reports of serious adverse liver reactions to the drug, including two deaths and two liver transplants.

“The TGA and its expert advisory committee, the Adverse Drug Reactions Advisory Committee (ADRAC), have urgently investigated these reports. ADRAC has today recommended the cancellation of the registration of Lumiracoxib due to the severity of the reported side effects associated with this drug,” Dr Hammett said.

“The TGA has taken this advice to cancel the registration of Lumiracoxib in order to prevent further cases of severe liver damage.

“It seems that the longer people are on the medicine, the greater the chance of liver injury. The TGA is, therefore, advising people to stop taking the Lumiracoxib immediately and to discuss alternative treatments with their doctor,” Dr Hammett said.^[9]

New Zealand has followed suit with Australia in recalling Prexige.^[10]

On October 3, 2007, Health Canada requested sales of Prexige to stop. Novartis has agreed to the request and has taken steps to do so.^[11] On December 13, 2007, the European Medicines Agency recommended the withdrawal for Prexige from all EU markets.^[12]

On January 17, 2008, the Philippines Department of Health ordered Novartis Healthcare Phils. Inc. (Novartis) to remove (recall) all lumiracoxib from local drug stores in 2 weeks due to the harmful effects of the drug (potential serious liver-related side effects, hepatotoxicity or malfunction of the lungs).^[13]

On July 22, 2008, The Brazilian National Health Surveillance Agency ordered the withdrawal of 100 mg formulations of lumiracoxib and suspended marketing of the 400 mg formulation for 90 days,^[14] after a three-year safety review found a marked increase in adverse event reports; 35% of lumiracoxib-associated adverse events reported worldwide between July 2005 and April 2008 were found to have occurred in Brazil.^[15] Lumiracoxib was definitively withdrawn from the Brazilian market on October 3, 2008.^[16]

On November 12, 2008, INVIMA, the Colombian National Institute for Food and Drug Surveillance ordered the withdrawal of all presentations of lumiracoxib (Prexige), due to the international reports on hepatotoxicity.

MECHANISM

Synthesis

The partial reduction of 4-methylanisole (I) with sodium in liquid ammonia / THF / ethanol gives the enol ether (II), which is condensed with 2-chloro-6-fluoroaniline (III) by means of TiCl4 in chlorobenzene / THF to yield the imine (IV), which, without isolation, is aromatized with I2 in AcOH / THF to provide N- (2-chloro-6-fluorophenyl) -N- (4-methylphenyl) amine (V). The acylation of ( V) with 2-chloroacetyl chloride (VI) at 90 C affords the 2-chloroacetamide (VII), which is cyclized by means of AlCl3 by heating at 160? C to afford 1- (2-chloro-6-fluorophenyl) -5 -methylindolin-2-one (VIII). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol / water and acidified with 1N HCl. Alternatively, the intermediate N- (2-chloro-6-fluorophenyl) -N- (4- methylphenyl) amine (V) can also be obtained by condensation of 2-chloro-N- (4-methylphenyl) acetamide (IX) with 2-chloro-6-fluorophenol (X) by means of K2CO3 in isopropanol to yield 2- ( 2-chloro-6-fluorophenoxy) -N- (4-methylphenyl) acetamide (XI), which is treated with MeONa in methanol to obtain the target secondary amine (V).

WO 0123346

The reduction of 2-iodo-5-methylbenzoic acid (I) with BH3/THF in THF gives 2-iodo-5-methylbenzyl alcohol (II), which is treated with refluxing 48% HBr to yield the benzyl bromide (III). Reaction of (III) with NaCN in ethanol/water afford the phenylacetonitrile (IV), which is hydrolyzed with NaOH in refluxing EtOH/water to provide the phenylacetic acid (V). Reaction of (V) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VI), which is treated with dimethylamine in diethyl ether/THF to yield 2-(2-iodo-5-methylphenyl)-N,N-dimethylacetamide (VII). Condensation of (VII) with 2-chloro-6-fluoroaniline (VIII) by means of Cu powder, Cu2I2 and K2CO3 in refluxing xylene affords 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]-N,N-dimethylacetamide (IX), which is finally hydrolyzed with NaOH in refluxing butanol/water.

JP 2001514244; US 6291523; WO 9911605

References

Shi, S; Klotz, U (March 2008). “Clinical use and pharmacological properties of selective COX-2 inhibitors.”. European Journal of Clinical Pharmacology 64 (3): 233–52.doi:10.1007/s00228-007-0400-7. PMID 17999057.
Tacconelli S, Capone ML, Patrignani P (2004). “Clinical pharmacology of novel selective COX-2 inhibitors”. Curr Pharm Des 10 (6): 589–601. doi:10.2174/1381612043453108.PMID 14965322.
Urgent medicine recall – Lumiracoxib (PREXIGE)
http://hugin.info/134323/R/1156327/223186.pdf
Withdrawal of Market Authorization for Prexige
Media releases
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_33_GG-FDA-Tab-U.pdf
Medicines Regulator cancels registration of anti inflammatory drug, Lumiracoxib, Therapeutic Goods Administration, 11 August 2007. Retrieved on 2007-08-11
http://www.tga.gov.au/media/2007/070811-lumiracoxib.htm
“NZ regulators ban arthritis drug”. The New Zealand Herald. 21 August 2007. Retrieved 12 September 2011.
http://www.novartis.ca/downloads/en/letters/prexige_fact_20071003_e.pdf
Press release: European Medicines Agency recommends withdrawal of the marketing authorisations for lumiracoxib-containing medicines, 13 December 2007
Abs-Cbn Interactive, DOH recalls lumiracoxib, sets two-week deadline
“Anvisa cancela registro do Prexige; consumidor deve substituir medicamento”. Folha de S. Paulo (in Portuguese). July 22, 2008. Retrieved 2008-07-22.
“Anvisa cancela registro do antiinflamatório Prexige” (Press release) (in Portuguese). Anvisa. July 22, 2008. Retrieved 2008-07-22.
“Anvisa suspende venda e uso de 2 antiinflamatórios” (in Portuguese). Terra. October 3, 2008. Retrieved 2008-10-03.

External links

ROFECOXIB

July 31, 2014 3:48 am / 2 Comments on ROFECOXIB

ROFECOXIB

MK-966, MK-0966, Vioxx

162011-90-7

C17-H14-O4-S

314.3596

Rofecoxib /ˌ r ɒ f ɨ ˈ k ɒ k s ɪ b / is a nonsteroidal anti-inflammatory drug (NSAID) that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea. Rofecoxib was approved by the Food and Drug Administration (FDA) on May 20, 1999, and was marketed under the brand names Vioxx, Ceoxx, and Ceeoxx.

Rofecoxib
Systematic (IUPAC) name


4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one
Clinical data
Pregnancy cat.	C (AU)
Legal status	Prescription Only (S4) (AU)withdrawn
Routes	oral
Pharmacokinetic data
Bioavailability	93%
Protein binding	87%
Metabolism	hepatic
Half-life	17 hours
Excretion	biliary/renal
Identifiers
CAS number	162011-90-7
ATC code	M01 AH02
PubChem	CID 5090
DrugBank	DB00533
ChemSpider	4911
UNII	0QTW8Z7MCR

Chemical data
Formula	C₁₇H₁₄O₄S
Mol. mass	314.357 g/mol

Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.^[1]

On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib’s risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease.^[2] Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.^[3] Merck reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and have set aside $4.85bn for legal claims from US citizens.

Rofecoxib was available on prescription in both tablet-form and as an oral suspension. It was available by injection for hospital use.

Mode of action

Pharmacokinetics

The therapeutic recommended dosages were 12.5, 25, and 50 mg with an approximate bioavailability of 93%.^[5]^[6]^[7] Rofecoxib crossed the placenta and blood–brain barrier,^[5]^[6]^[8]and took 1–3 hours to reach peak plasma concentration with an effective half-life (based on steady-state levels) of approximately 17 hours.^[5]^[7]^[9] The metabolic products are cis-dihydro and trans-dihydro derivatives of rofecoxib^[5]^[9] which are primarily excreted through urine.

Fabricated efficacy studies

On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that data for 21 studies he had authored for the efficacy of the drug (along with others such as celecoxib) had been fabricated in order to augment the analgesic effects of the drugs. There is no evidence that Reuben colluded with Merck in falsifying his data. Reuben was also a former paid spokesperson for the drug company Pfizer (which owns the intellectual property rights for marketing celecoxib in the United States). The retracted studies were not submitted to either the FDA or the European Union’s regulatory agencies prior to the drug’s approval. Drug manufacturer Merckhad no comment on the disclosure.^[10]

Adverse drug reactions

Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse effect profile to other NSAIDs.

Prostaglandin is a large family of lipids. Prostaglandin I2/PGI2/prostacyclin is just one member of it. Prostaglandins other than PGI2 (such as PGE2) also play important roles in vascular tone regulation. Prostacyclin/thromboxane are produced by both COX-1 and COX-2, and rofecoxib suppresses just COX-2 enzyme, so there is no reason to believe that prostacyclin levels are significantly reduced by the drug. And there is no reason to believe that only the balance between quantities of prostacyclin and thromboxane is the determinant factor for vascular tone.^[11] Indeed Merck has stated that there was no effect on prostacyclin production in blood vessels in animal testing.^[12] Other researchers have speculated that the cardiotoxicity may be associated with maleic anhydride metabolites formed when rofecoxib becomes ionized under physiological conditions. (Reddy & Corey, 2005)

Adverse cardiovascular events

VIGOR study and publishing controversy

The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., which compared the efficacy and adverse effect profiles of rofecoxib and naproxen, had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the study. The elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from cardiovascular events between the two groups, nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was by the patients at higher risk of heart attack, i.e. those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, or coronary artery bypass).

Merck’s scientists interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks “is primarily due to” this protective effect (Targum, 2001). Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference (Michaels 2005), and some outside scientists warned Merck that this claim was implausible before VIGOR was published.^[13] No evidence has since emerged for such a large cardioprotective effect of naproxen, although a number of studies have found protective effects similar in size to those of aspirin.^[14]^[15] Though Dr. Topol’s 2004 paper criticized Merck’s naproxen hypothesis, he himself co-authored a 2001 JAMA article stating “because of the evidence for an antiplatelet effect of naproxen, it is difficult to assess whether the difference in cardiovascular event rates in VIGOR was due to a benefit from naproxen or to a prothrombotic effect from rofecoxib.” (Mukherjee, Nissen and Topol, 2001.)

The results of the VIGOR study were submitted to the United States Food and Drug Administration (FDA) in February 2001. In September 2001, the FDA sent a warning letter to the CEO of Merck, stating, “Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen).”^[16] This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke).

Months after the preliminary version of VIGOR was published in the New England Journal of Medicine, the journal editors learned that certain data reported to the FDA were not included in the NEJM article. Several years later, when they were shown a Merck memo during the depositions for the first federal Vioxx trial, they realized that these data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data.^[17] They released the editorial to the media on December 8, 2005, before giving the authors a chance to respond. NEJM editor Gregory Curfman explained that the quick release was due to the imminent presentation of his deposition testimony, which he feared would be misinterpreted in the media. He had earlier denied any relationship between the timing of the editorial and the trial. Although his testimony was not actually used in the December trial, Curfman had testified well before the publication of the editorial.^[18]

The editors charged that “more than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR article.” These additional data included three additional heart attacks, and raised the relative risk of Vioxx from 4.25-fold to 5-fold. All the additional heart attacks occurred in the group at low risk of heart attack (the “aspirin not indicated” group) and the editors noted that the omission “resulted in the misleading conclusion that there was a difference in the risk of myocardial infarction between the aspirin indicated and aspirin not indicated groups.” The relative risk for myocardial infarctions among the aspirin not indicated patients increased from 2.25 to 3 (although it remained statitistically insignificant). The editors also noted a statistically significant (2-fold) increase in risk for serious thromboembolic events for this group, an outcome that Merck had not reported in the NEJM, though it had disclosed that information publicly in March 2000, eight months before publication.^[19]

The authors of the study, including the non-Merck authors, responded by claiming that the three additional heart attacks had occurred after the prespecified cutoff date for data collection and thus were appropriately not included. (Utilizing the prespecified cutoff date also meant that an additional stroke in the naproxen population was not reported.) Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label. They further noted that all of the data in the “omitted” table were printed in the text of the article. The authors stood by the original article.^[20]

NEJM stood by its editorial, noting that the cutoff date was never mentioned in the article, nor did the authors report that the cutoff for cardiovascular adverse events was before that for gastrointestinal adverse events. The different cutoffs increased the reported benefits of Vioxx (reduced stomach problems) relative to the risks (increased heart attacks).^[19]

Some scientists have accused the NEJM editorial board of making unfounded accusations.^[21]^[22] Others have applauded the editorial. Renowned research cardiologist Eric Topol,^[23] a prominent Merck critic, accused Merck of “manipulation of data” and said “I think now the scientific misconduct trial is really fully backed up”.^[24] Phil Fontanarosa, executive editor of the prestigious Journal of the American Medical Association, welcomed the editorial, saying “this is another in the long list of recent examples that have generated real concerns about trust and confidence in industry-sponsored studies”.^[25]

On May 15, 2006, the Wall Street Journal reported that a late night email, written by an outside public relations specialist and sent to Journal staffers hours before the Expression of Concern was released, predicted that “the rebuke would divert attention to Merck and induce the media to ignore the New England Journal of Medicine‘s own role in aiding Vioxx sales.”^[26]

“Internal emails show the New England Journal’s expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal’s handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article.” The Journal stated that NEJM‘s “ambiguous” language misled reporters into incorrectly believing that Merck had deleted data regarding the three additional heart attacks, rather than a blank table that contained no statistical information; “the New England Journal says it didn’t attempt to have these mistakes corrected.”^[26]

Alzheimer’s studies

In 2000 and 2001, Merck conducted several studies of rofecoxib aimed at determining if the drug slowed the onset of Alzheimer’s disease. Merck has placed great emphasis on these studies on the grounds that they are relatively large (almost 3000 patients) and compared rofecoxib to a placebo rather than to another pain reliever. These studies found an elevated death rate among rofecoxib patients, although the deaths were not generally heart-related. However, they did not find any elevated cardiovascular risk due to rofecoxib.^[27] Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of rofecoxib’s safety.

APPROVe study

In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three-year trial with the primary aim of evaluating the efficacy of rofecoxib for theprophylaxis of colorectal polyps. Celecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib.

The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (includingheart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Moreover, overall and cardiovascular mortality rates were similar between the rofecoxib and placebo populations.^[28]

In summary, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo.

Other studies

Pre-approval Phase III clinical trials, like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for the first eighteen months of rofecoxib usage (Merck, 2004). Others have pointed out that “study 090,” a pre-approval trial, showed a 3-fold increase in cardiovascular events compared to placebo, a 7-fold increase compared to nabumetone (another [NSAID]), and an 8-fold increase in heart attacks and strokes combined compared to both control groups.^[29]^[30] Although this was a relatively small study and only the last result was statistically significant, critics have charged that this early finding should have prompted Merck to quickly conduct larger studies of rofecoxib’s cardiovascular safety. Merck notes that it had already begun VIGOR at the time Study 090 was completed. Although VIGOR was primarily designed to demonstrate new uses for rofecoxib, it also collected data on adverse cardiovascular outcomes.

Several very large observational studies have also found elevated risk of heart attack from rofecoxib. For example, a recent retrospective study of 113,000 elderly Canadians suggested a borderline statistically significant increased relative risk of heart attacks of 1.24 from Vioxx usage, with a relative risk of 1.73 for higher-dose Vioxx usage. (Levesque, 2005). Another study, using Kaiser Permanente data, found a 1.47 relative risk for low-dose Vioxx usage and 3.58 for high-dose Vioxx usage compared to current use of celecoxib, though the smaller number was not statistically significant, and relative risk compared to other populations was not statistically significant. (Graham, 2005).

Furthermore, a more recent meta-study of 114 randomized trials with a total of 116,000+ participants, published in JAMA, showed that Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia.^[31]

Other COX-2 inhibitors

Any increased risk of renal and arrhythmia pathologies associated with the class of COX-2 inhibitors, e.g. celecoxib (Celebrex), valdecoxib (Bextra), parecoxib (Dynastat),lumiracoxib, and etoricoxib is not evident,^[31] although smaller studies^[32]^[33] had demonstrated such effects earlier with the use of celecoxib, valdecoxib and parecoxib.

Nevertheless, it is likely that trials of newer drugs in the category will be extended in order to supply additional evidence of cardiovascular safety. Examples are some more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige), which are currently (circa 2005) undergoing Phase III/IV clinical trials.

Besides, regulatory authorities worldwide now require warnings about cardiovascular risk of COX-2 inhibitors still on the market. For example, in 2005, EU regulators required the following changes to the product information and/or packaging of all COX-2 inhibitors:^[34]

Contraindications stating that COX-2 inhibitors must not be used in patients with established ischaemic heart disease and/or cerebrovascular disease (stroke), and also in patients with peripheral arterial disease
Reinforced warnings to healthcare professionals to exercise caution when prescribing COX-2 inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and smoking
Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment

Other NSAIDs

Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with not only other COX-2 inhibitiors, but even the majority of other NSAIDs. It is only with the recent development of drugs like Vioxx that drug companies have carried out the kind of well executed trials that could establish such effects and these sort of trials have never been carried out in older “trusted” NSAIDs such as ibuprofen, diclofenac and others. The possible exceptions may be aspirin and naproxen due to their anti-platelet aggregation properties.

Withdrawal

Due to the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.^[35]

In addition to its own studies, on September 23, 2004 Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market.^[36]

On November 5, the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (Jüni et al., 2004). The authors concluded that, owing to the known cardiovascular risk, rofecoxib should have been withdrawn several years earlier. The Lancet published an editorial which condemned both Merck and the FDA for the continued availability of rofecoxib from 2000 until the recall. Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis that noted that Jüni omitted several studies that showed no increased cardiovascular risk. (Merck & Co., 2004).

In 2005, advisory panels in both the U.S. and Canada encouraged the return of rofecoxib to the market, stating that rofecoxib’s benefits outweighed the risks for some patients. The FDA advisory panel voted 17-15 to allow the drug to return to the market despite being found to increase heart risk. The vote in Canada was 12-1, and the Canadian panel noted that the cardiovascular risks from rofecoxib seemed to be no worse than those from ibuprofen—though the panel recommended that further study was needed for all NSAIDs to fully understand their risk profiles. Notwithstanding these recommendations, Merck has not returned rofecoxib to the market.^[37]

In 2005, Merck retained Debevoise & Plimpton LLP to investigate Vioxx study results and communications conducted by Merck. Through the report, it was found that Merck’s senior management acted in good faith, and that the confusion over the clinical safety of Vioxx was due to the sales team’s overzealous behavior. The report that was filed gave a timeline of the events surrounding Vioxx and showed that Merck intended to operate honestly throughout the process. Any mistakes that were made regarding the mishandling of clinical trial results and withholding of information was the result of oversight, not malicious behavior. The Martin Report did conclude that the Merck’s marketing team exaggerated the safety of Vioxx and replaced truthful information with sales tactics.^{[citation needed]} The report was published in February 2006, and Merck was satisfied with the findings of the report and promised to consider the recommendations contained in the Martin Report. Advisers to the US Food and Drug Administration (FDA) have voted, by a narrow margin, that it should not ban Vioxx — the painkiller withdrawn by drug-maker Merck.

They also said that Pfizer’s Celebrex and Bextra, two other members of the family of painkillers known as COX-2 inhibitors, should remain available, despite the fact that they too boost patients’ risk of heart attack and stroke. url = http://www.nature.com/drugdisc/news/articles/433790b.html The recommendations of the arthritis and drug safety advisory panel offer some measure of relief to the pharmaceutical industry, which has faced a barrage of criticism for its promotion of the painkillers. But the advice of the panel, which met near Washington DC over 16–18 February, comes with several strings attached.

For example, most panel members said that manufacturers should be required to add a prominent warning about the drugs’ risks to their labels; to stop direct-to-consumer advertising of the drugs; and to include detailed, written risk information with each prescription. The panel also unanimously stated that all three painkillers “significantly increase the risk of cardiovascular events”.

The panel voted 17 to 15 against banning Vioxx (rofecoxib) entirely; the vote on Bextra (valdecoxib) was 17 to 13 with 2 abstentions; Celebrex (celecoxib) was endorsed 31 to 1. Shares of Merck, based in Whitehouse Station, New Jersey, and New York-based Pfizer closed up 13% and 7% respectively on 18 February, 2013, the day of the votes.

The FDA is expected to act on the recommendations within weeks. Although the agency usually follows the recommendations of its outside advisers, it is not bound to do so. A top official said that, in light of the closeness of some of the votes, the agency will examine the panel members’ comments in detail before deciding what to do.

An official from Merck said during the meeting that it would consider reintroducing Vioxx, which it withdrew in September 2004. On April 7, 2005, Pfizer withdrew Bextra from the U.S. market on recommendation by the FDA. Pfizer’s other painkiller, Celebrex, is still on the market.

Litigation

As of March 2006, there had been over 10,000 cases and 190 class actions filed against Merck^{[citation needed]} over adverse cardiovascular events associated with rofecoxib and the adequacy of Merck’s warnings. The first wrongful death trial, Rogers v. Merck, was scheduled in Alabama in the spring of 2005, but was postponed after Merck argued that the plaintiff had falsified evidence of rofecoxib use.[1]

On August 19, 2005, a jury in Texas voted 10-2 to hold Merck liable for the death of Robert Ernst, a 59-year-old man who allegedly died of a rofecoxib-induced heart attack. The plaintiffs’ lead attorney was Mark Lanier. Merck argued that the death was due to cardiac arrhythmia, which had not been shown to be associated with rofecoxib use. The jury awarded Carol Ernst, widow of Robert Ernst, $253.4 million in damages. This award will almost certainly be capped at no more than US$26.1 million because of punitive damages limits under Texas law.[2] As of March 2006, the plaintiff had yet to ask the court to enter a judgment on the verdict; Merck has stated that it will appeal.

On November 3, 2005, Merck won the second case Humeston v. Merck, a personal injury case, in Atlantic City, New Jersey. The plaintiff experienced a mild myocardial infarction and claimed that rofecoxib was responsible, after having taken it for two months. Merck argued that there was no evidence that rofecoxib was the cause of Humeston’s injury and that there is no scientific evidence linking rofecoxib to cardiac events with short durations of use. The jury ruled that Merck had adequately warned doctors and patients of the drug’s risk.[3]

The first federal trial on rofecoxib, Plunkett v. Merck, began on November 29, 2005 in Houston. The trial ended in a hung jury and a mistrial was declared on December 12, 2005. According to the Wall Street Journal, the jury hung by an eight to one majority, favoring the defense. Upon retrial in February 2006 in New Orleans, where the Vioxx multidistrict litigation (MDL) is based, a jury found Merck not liable, even though the plaintiffs had the NEJM editor testify as to his objections to the VIGOR study.

On January 30, 2006, a New Jersey state court dismissed a case brought by Edgar Lee Boyd, who blamed Vioxx for gastrointestinal bleeding that he experienced after taking the drug. The judge said that Boyd failed to prove the drug caused his stomach pain and internal bleeding.

In January 2006, Garza v. Merck began trial in Rio Grande City, Texas. The plaintiff, a 71-year-old smoker with heart disease, had a fatal heart attack three weeks after finishing a one-week sample of rofecoxib. On April 21, 2006 the jury awarded the plaintiff $7 million compensatory and $25 million punitive. The Texas state court of appeals in San Antonio later rules Garza’s fatal heart attack probably resulted from pre-existing health conditions unrelated to his taking of Vioxx, thus reversing the $32 million jury award.[4]

On April 5, 2006, the jury held Merck liable for the heart attack of 77-year-old John McDarby, and awarded Mr McDarby $4.5 million in compensatory damages based on Merck’s failure to properly warn of Vioxx safety risks. After a hearing on April 11, 2006, the jury also awarded Mr McDarby an additional $9 million in punitive damages. The same jury found Merck not liable for the heart attack of 60-year-old Thomas Cona, a second plaintiff in the trial, but was liable for fraud in the sale of the drug to Cona.

Merck has reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and have set aside $4.85bn for legal claims from US citizens. Patients who claim to have suffered as a result of taking Vioxx in countries outside the US are campaigning for this to be extended.

In March 2010, an Australian class-action lawsuit against Merck ruled that Vioxx doubled the risk of heart attacks, and that Merck had breached the Trade Practices Act by selling a drug which was unfit for sale.^[38]

In November 2011, Merck announced a civil settlement with the US Attorney’s Office for the District of Massachusetts, and individually with 43 US states and the District of Columbia, to resolve civil claims relating to Vioxx.[5] Under the terms of the settlement, Merck agreed to pay two-thirds of a previously recorded $950 million reserve charge in exchange for release from civil liability. Litigation with seven additional states remains outstanding. Under separate criminal proceedings, Merck plead guilty to a federal misdemeanor charge relating to the marketing of the drug across state lines, incurring a fine of $321.6 million.[6]

Other effects

Rofecoxib was shown to improve premenstrual acne vulgaris in a placebo controlled study.^[39]

Synthesis

Rofecoxib synthesis.^[40]

,,,,,,,,,,,,,,,,,

The oxidation of 4- (methylsulfanyl) acetophenone (X) with monoperoxyphthalic acid (MMPP) in dichloro-methane / methanol gives the corresponding sulfone (XI), which is brominated with Br2 / AlCl3 in chloroform, yielding the expected phenacyl bromide ( XII). Finally, this compound is cyclocondensed with phenylacetic acid (I) by means of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and triethylamine in acetonitrile. 5) Reaction of [4- (methylsulfonyl ) phenyl] phenylacetyl-ene (XIII) with CO catalyzed by Rh4 (CO) 12 in THF at 100 C in a stainless steel autoclave at 100 Atm pressure, followed by a chromatographic separation in a silicagel column to eliminate the undesired regioisomer.

……………….

The synthesis of rofecoxib can be performed by several different ways: 1) The condensation of phenylacetic acid (I) with ethyl bromoacetate (II) by means of triethylamine in THF yields 2- (phenylacetoxy) acetic acid ethyl ester (III), which is cyclized to the hydroxyfuranone (IV) by means of potassium tert-butoxide in tert-butanol. The reaction of (IV) with triflic anhydride and diisopropylethylamine in dichloro-methane affords the corresponding triflate (V), which by reaction with LiBr in hot acetone yields the bromofuranone (VI) The condensation of (VI) with 4- (methylsulfanyl) phenylboronic acid (VII) by means of Na2CO3 and Pd (Ph3P) 4 in hot toluene gives 4- [4- (methylsulfanyl) -phenyl]. – 3-phenylfuran-2 (5H) -one (VIII), which is finally oxidized with 2KHSO5.KHSO4.K2SO4 (oxone). 2) The intermediate (VIII) can also be obtained by condensation of triflate (V) with boronic acid ( VII) by means of Na2CO3 and Pd (Ph3P) 4 in hot toluene. 3) The intermediate (VIII) can also be synthesized by the reaction of triflate (V) with tetramethylammonium chloride, giving the chlorofuranone (IX), which is then condensed with boronic acid (VII) as before.

Footnotes

Jump up^ http://www.npr.org/templates/story/story.php?storyId=4054991
Jump up^ “Up to 140,000 heart attacks linked to Vioxx.”. New Scientist. 2005-01-25. p. 1.
Jump up^ “Merck Sees Slightly Higher 2007 Earnings”. New York Times. Reuters. 2006-12-07. p. A1.
Jump up^ Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M. B.; Hawkey, C. J.; Hochberg, M. C.; Kvien, T. K.; Schnitzer, T. J.; Vigor Study, G. (2000). “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis”. New England Journal of Medicine 343 (21): 1520–1528, 2 1528 following 1528. doi:10.1056/NEJM200011233432103. PMID 11087881. edit
^ Jump up to:^a ^b ^c ^d Merck & Co. VIOXX (rofecoxib tablets and oral suspension). Accessed at: http://www.merck.com/product/usa/pi_circulars/v/vioxx/vioxx_pi.pdf 01 Feb 2010
^ Jump up to:^a ^b Gold Standard Inc. Rofecoxib Vioxx Accessed at: http://www.mdconsult.com/das/pharm/body/181267313-3/946823742/full/2399 01 Feb 2010
^ Jump up to:^a ^b Davies, N. M.; Teng, X. W.; Skjodt, N. M. (2003). “Pharmacokinetics of rofecoxib: a specific cyclo-oxygenase-2 inhibitor”. Clinical pharmacokinetics 42 (6): 545–556.PMID 12793839. edit
Jump up^ Padi, S.; Kulkarni, S. (2004). “Differential effects of naproxen and rofecoxib on the development of hypersensitivity following nerve injury in rats”. Pharmacology, Biochemistry, and Behavior 79 (2): 349–358. doi:10.1016/j.pbb.2004.08.005. PMID 15501312. edit
^ Jump up to:^a ^b Scott, L. J.; Lamb, H. M. (1999). “Rofecoxib”. Drugs 58 (3): 499–505; discussion 506–7. doi:10.2165/00003495-199958030-00016. PMID 10493277. edit
Jump up^ Winstein, Keith J. (March 11, 2009). “Top Pain Scientist Fabricated Data in Studies, Hospital Says”. The Wall Street Journal.
Jump up^ Vane, J.; Bakhle, Y.; Botting, R. (1998). “Cyclooxygenases 1 and 2”. Annual review of pharmacology and toxicology 38: 97–120. doi:10.1146/annurev.pharmtox.38.1.97.PMID 9597150. edit
Jump up^ sfgate.com
Jump up^ www.saferdrugsnow.org
Jump up^ Karha, J.; Topol, E. J. (2004). “The sad story of Vioxx, and what we should learn from it”. Cleveland Clinic journal of medicine 71 (12): 933–934, 936, 934–9.doi:10.3949/ccjm.71.12.933. PMID 15641522. edit
Jump up^ Solomon, D. H.; Glynn, R. J.; Levin, R.; Avorn, J. (2002). “Nonsteroidal anti-inflammatory drug use and acute myocardial infarction”. Archives of Internal Medicine 162 (10): 1099–1104.doi:10.1001/archinte.162.10.1099. PMID 12020178. edit
Jump up^http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM166383.pdf
Jump up^ Curfman, G.; Morrissey, S.; Drazen, J. (2005). “Expression of concern: Bombardier et al., “Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis,” N Engl J Med 2000;343:1520-8″. The New England Journal of Medicine 353 (26): 2813–2814. doi:10.1056/NEJMe058314. PMID 16339408. edit
Jump up^ http://www.forbes.com/work/feeds/ap/2006/02/13/ap2523250.html. Missing or empty |title= (help)^{[dead link]}
^ Jump up to:^a ^b Curfman, G.; Morrissey, S.; Drazen, J. (2006). “Expression of concern reaffirmed”. The New England Journal of Medicine 354 (11): 1193. doi:10.1056/NEJMe068054.PMID 16495386. edit
Jump up^ Bombardier, C.; Laine, L.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M.; Hawkey, C.; Hochberg, M.; Kvien, T.; Schnitzer, T. J.; Weaver, A. (2006). “Response to expression of concern regarding VIGOR study”. The New England Journal of Medicine 354 (11): 1196–1199. doi:10.1056/NEJMc066096. PMID 16495387. edit
Jump up^ http://pipeline.corante.com/archives/2006/02/22/nejm_vs_its_contributors_round_two.php
Jump up^ http://dimer.tamu.edu/simplog/archive.php?blogid=3&pid=3293
Jump up^ http://genetics.case.edu/faculty2.php?fac=ejt9
Jump up^ http://www.medicinenet.com/script/main/art.asp?articlekey=56384&page=2
Jump up^ http://www.beasleyallen.com/news/vioxx-plaintiffs-seek-mistrial-after-allegation-on-merck-study/
^ Jump up to:^a ^b David Armstrong (2006-05-15). “How the New England Journal Missed Warning Signs on Vioxx”. Wall Street Journal. p. A1.
Jump up^ Konstam, M. A.; Weir, M. R.; Reicin, A.; Shapiro, D.; Sperling, R. S.; Barr, E.; Gertz, B. J. (2001). “Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib”. Circulation104 (19): 2280–2288. doi:10.1161/hc4401.100078. PMID 11696466. edit
Jump up^ Bresalier, R.; Sandler, R.; Quan, H.; Bolognese, J.; Oxenius, B.; Horgan, K.; Lines, C.; Riddell, R.; Morton, D.; Lanas, A.; Konstam, M. A.; Baron, J. A.; Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators (2005). “Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial”. The New England Journal of Medicine 352(11): 1092–1102. doi:10.1056/NEJMoa050493. PMID 15713943. edit
Jump up^ http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf
Jump up^ Wolfe, M. M. (2004). “Rofecoxib, Merck, and the FDA”. The New England Journal of Medicine 351 (27): 2875–2878; author 2878 2875–2878. doi:10.1056/NEJM200412303512719.PMID 15625749. edit
^ Jump up to:^a ^b Zhang, J.; Ding, E.; Song, Y. (2006). “Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials”. Journal of the American Medical Association 296 (13): 1619–1632. doi:10.1001/jama.296.13.jrv60015. PMID 16968832. edit
Jump up^ Solomon, S.; McMurray, J.; Pfeffer, M.; Wittes, J.; Fowler, R.; Finn, P.; Anderson, W.; Zauber, A.; Hawk, E.; Bertagnolli, M.; Adenoma Prevention with Celecoxib (APC) Study Investigators (2005). “Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention”. The New England Journal of Medicine 352 (11): 1071–1080.doi:10.1056/NEJMoa050405. PMID 15713944. edit
Jump up^ Nussmeier, N.; Whelton, A.; Brown, M.; Langford, R.; Hoeft, A.; Parlow, J.; Boyce, S.; Verburg, K. (2005). “Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery”. The New England Journal of Medicine 352 (11): 1081–1091. doi:10.1056/NEJMoa050330. PMID 15713945. edit
Jump up^ “European Medicines Agency concludes action on COX-2 inhibitors” (pdf). European Medicines Agency. Retrieved 2008-04-16.
Jump up^ “Merck Announces Voluntary Worldwide Withdrawal of VIOXX” (pdf). Retrieved 2008-04-16.
Jump up^ “Congress Questions Vioxx, FDA”. PBS NewsHour. 2004-11-18. Retrieved 2013-06-03.
Jump up^ “SUMMARY: Report of the Expert Advisory Panel on the Safety of Cox-2 Selective Non-steroidal Anti-Inflammatory Drugs (NSAIDs)”. Health Canada. 2005-07-06. Retrieved 2011-06-04.
Jump up^ Drug unfit for sale, says judge in compo case The Age, March 6, 2010
Jump up^ http://bioline.utsc.utoronto.ca/archive/00002693/01/dv04120.pdf#search=%22acne%20rofecoxib%22
Jump up^ http://vioxxlawyer.org/rofecoxib-synthesis/

References

FDA (2005). “Summary minutes for the February 16, 17 and 18, 2005, Joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee.” Published on the internet, March 2005. Link
Fitzgerald GA, Coxibs and Cardiovascular Disease, N Engl J Med 2004;351(17): 1709–1711. PMID 15470192.
Grassley CE (15 Oct 2004). Grassley questions Merck about communication with the FDA on Vioxx. Press Release.
Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M (2004). Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet (published online; see also Merck response below)
Karha J and Topol EJ. The sad story of Vioxx, and what we should learn from it Cleve Clin J Med 2004; 71(12):933-939. PMID 15641522
Michaels, D. (June 2005) DOUBT Is Their Product, Scientific American, 292 (6).
Merck & Co., (5 Nov 2004). Response to Article by Juni et al. Published in The Lancet on Nov. 5. Press Release.
Merck & Co (30 Sep 2004) Merck Announces Voluntary Worldwide Withdrawal of VIOXX. Press release [7].
D. M. Mukherjee, S. E. Nissen, and E. J. Topol, “Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors,” Journal of the American Medical Association 186 (2001): 954–959.
Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352(11):1081-91. PMID 15713945
Okie, S (2005) “Raising the safety bar–the FDA’s coxib meeting.” N Engl J Med. 2005 Mar 31;352(13):1283-5. PMID 15800221.
Leleti Rajender Reddy, Corey EJ. Facile air oxidation of the conjugate base of rofecoxib (Vioxx), a possible contributor to chronic human toxicity Tetrahedron Lett 2005, 46: 927. doi:10.1016/j.tetlet.2004.12.055
Swan SK et al., Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt Diet. Annals of Int Med 2000; 133:1–9
Targum, SL. (1 Feb. 2001) Review of cardiovascular safety database. FDA memorandum. [8]
Wolfe, MM et al., Gastrointestinal Toxicity of Nonsteroidal Anti-anflamattory Drugs, New England Journal of Medicine. 1999; 340; 1888-98.

External links

National Public Radio 2004 Q&A on the case, following withdrawal announcement
Court TV’s full coverage of the Vioxx civil trials
Merck website on Vioxx litigation
FDA Public Health Advisory on Vioxx
David Michaels. Doubt is Their Product Scientific American, June 2004, p. 96-101
JURIST, Much Pain, Much Gain: Skeptical Ruminations on the Vioxx Litigation
Ted Frank, American Enterprise Institute, The Vioxx Litigation, Part I and Part II, December 2005
briandeer.com – Vioxx: the UK connection
Campaign for compensation for Vioxx victims outside the US

Cimicoxib

July 30, 2014 9:06 am / Leave a comment

Cimicoxib

UR-8880,

CAS 265114-23-6,

Molecular Formula: C₁₆H₁₃ClFN₃O₃S

Molecular Weight: 381.809123

Uriach (Originator)

4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol-1-yl]benzenesulfonamide

IN PHASE 2

Cimicoxib (trade name Cimalgex) is a non-steroidal anti-inflammatory drug (NSAID) used in veterinary medicine to treat dogs for pain and inflammation associated with osteoarthritis and for the management of pain and inflammation associated with surgery.^[1] It acts as a COX-2 inhibitor.

Cimicoxib is a selective COX-2 inhibitor being developed by Affectis as a treatment for depression and schizophrenia. If approved, Cimicoxib would be the first drug in decades to treat depression by a new mechanism of action

Cimicoxib, an imidazole derivative, is a selective cyclooxygenase-2 (COX-2) inhibitor. The product was in phase II development at Affectis Pharmaceuticals for the oral treatment of major depression, however, no recent development have been reported. Originally developed by Uriach, the compound was acquired by Palau Pharma, a spin-off created by Uriach in November 2006.

In 2007, Palau Pharma licensed global rights to cimicoxib to Affectis Pharmaceuticals for all CNS indications. Palau had been clinically evaluating the compound for the treatment of osteoarthritis, pain and rheumatoid arthritis, however, no recent development has been reported for these indications. The compound holds potential for the treatment of schizophrenia.

Chemical structure for CID 213053

Treatment of 4-(acetylamino)phenylsulfonyl chloride (I) with tert-butylamine yields sulfonamide (II), which on deprotection with potassium hydroxide gives amine (III). Reaction of compound (III) with 4-methoxy-3-fluorobenz-aldehyde gives imine (IV), which is cyclized with tosylmethyl isocyanide to afford imidazole (V). Regioselective chlorination of compound (V) with N-chlorosuccinimide (NCS) to afford the chloroimidazole (VI) and then deprotection of the sulfonamide group of (VI) yields cimicoxib in 40% overall yield.

EP 1122243; JP 2002527508; WO 0023426, ES 2184633; WO 0316285

……………………………….

http://www.google.com/patents/EP1424329A1?cl=en

EXAMPLE 1

4-Amino-N- tert -butylbenzenesulfonamide Method A:

[0031]

a) N-tert-Butyl-4-nitrobenzenesulfonamide

[0032]

To a solution of tert-butylamine (0.47 L, 6.4 mol) in THF (0.55 L) is slowly added, at 0 °C, a solution of 4-nitrobenzenesulfonyl chloride (50 g, 0.23 mol) in THF (0.55 L) and the resulting mixture is stirred for 24 h at room temperature. The solvent is removed and the residue is taken up in a CHCl₃/0.5 N HCl mixture, the layers are separated and the aqueous phase is extracted with CHCl₃. The combined organic extracts are washed with H₂O and brine and dried over MgSO₄. The solvent is removed, yielding 56.3 g of a yellowish solid which is directly used in the next reaction (yield: 97%).
Mp: 105-109°C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.29 (s, 9 H), 5.07 (s, 1 H), 8.13 (d, J = 9 Hz, 2 H), 8.39 (d, J = 9 Hz, 2 H).

b) Title compound

[0033]

A solution of N-tert-butyl-4-nitrobenzenesulfonamide (10.0 g, 39 mmol) in EtOH (100 mL) is stirred for 48 h under a H₂ atmosphere in the presence of 10% Pd/C (1.50 g). The resulting mixture is filtered and concentrated to give the desired product as a slightly-coloured solid (8.7 g, yield: 98%).
Mp: 127 °C; ¹H-NMR (300 MHz, CDCl₃ + CD₃OD) δ (TMS): 1.19 (s, 9 H), 3.74 (s, CD₃OD + 1 H), 6.93 (d, J = 9 Hz, 2 H), 7.66 (d, J = 9 Hz, 2 H).

Method B:

[0034]

a) 4-Acetylamino-N-tert-butylbenzenesulfonamide

[0035]

To a suspension of 4-acetylaminobenzenesulfonyl chloride (10 g, 43 mmol) in DME (103 mL) is added, at 0 °C, tert-butylamine (9 mL, 86 mmol) in DME (103 mL). Next, the reaction mixture is stirred for 4 h at reflux. The solvent is removed and CHCl₃ is added. The resulting suspension is filtered and the solid is washed with CHCl₃, H₂O and Et₂O. The solid obtained is dried in vacuo to give 8.0 g of the product as a white solid (yield: 68%).
Mp: 200-201 °C; ¹H-NMR (300 MHz, CDCl₃ + CD₃OD) δ (TMS): 1.15 (s, 9 H), 2.12 (s, 3 H), 4.21 (s, 2H + CD₃OD), 7.66 (d, J = 9 Hz, 2 H), 7.75 (d, J = 9 Hz, 2 H).

b) Title compound

[0036]

A solution of 4-acetylamino-N-tert-butylbenzenesulfonamide (8.0 g, 29.6 mmol), KOH (8.30 g, 148 mmol), H₂O (6 mL) and MeOH (24 mL) is heated at 100°C for 2 h. H₂O (24 mL) is added and the mixture is heated for two more hours. It is allowed to cool, H₂O is added and it is brought to pH 8 with 1N HCl. It is then extracted with EtOAc, dried over Na₂SO₄ and the solvent is removed, to give 6.0 g of the product as a white solid (yield: 89%).

EXAMPLE 2 N- tert -Butyl-4-[(3-fluoro-4-methoxybenzylidene)amino]benzenesulfonamide

[0037]
[0038]

A mixture of 4-amino-N-tert-butylbenzenesulfonamide (52.3 g, 0.23 mol, obtained in example 1), 3-fluoro-4-methoxybenzaldehyde (35.3 g, 0.23 mol) and toluene (2.5 L) is heated at reflux in a Dean-Stark for 24 h. The solvent is removed, yielding 83.5 g of the title compound (yield: quantitative).
Mp: 129-131 °C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.23 (s, 9 H), 3.98 (s, 3 H), 4.65 (s, 1 H), 7.04 (t, J = 8.1 Hz, 1 H), 7.21 (d, J = 6.7 Hz, 2 H), 7.58 (m, 1 H), 7.73 (dd, J_H-F = 11.8 Hz, J = 2 Hz, 1 H), 7.90 (d, J = 6.7 Hz, 2 H), 8.33 (s, 1 H).

EXAMPLE 3 N-tert-Butyl-4-[5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

[0039]
[0040]

A mixture of N-tert-butyl-4-[(3-fluoro-4-methoxybenzylidene)amino]benzenesulfonamide (41.5 g, 114 mmol, obtained in example 2), tosylmethylisocyanide (33.22 g, 171 mmol), K₂CO₃ (31.1 g, 228 mmol), DME (340 mL) and MeOH (778 mL) is heated at reflux for 3 h. The solvent is removed and the residue is taken up in a CHCl₃/H₂O mixture and the layers are separated. The aqueous phase is extracted with CHCl₃ and the combined organic extracts are dried over MgSO₄ and concentrated. A crude product is obtained, which is washed with Et₂O several times to give 41.40 g of a creamy solid that is directly used in the next reaction (yield: 90%).
Mp: 229-232°C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.24 (s, 9 H), 3.89 (s, 3 H), 4.51 (s, 1 H), 6.90 (m, 3 H), 7.23 (s, 1 H), 7.29 (d, J = 8.7 Hz, 2 H), 7.73 (s, 1 H), 7.94 (d, J = 8.7 Hz, 2 H).

EXAMPLE 4 N-tert-Butyl-4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

[0041]
[0042]

A mixture of N-tert-butyl-4-[5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (41.40 g, 103 mmol, obtained in example 3) and acetonitrile (840 mL) is heated at reflux and acetonitrile is added until complete dissolution (200 mL more). Next, N-chlorosuccinimide (15.0 g, 113 mmol) is added and the mixture is refluxed for 24 h. The solvent is removed and the residue is suspended in EtOAc and 1N HCl and is stirred for 10 min. The solid obtained is filtered and washed directly in the filter with 1N HCl, 1N NaOH, saturated NH₄Cl solution, H₂O and Et₂O. A solid is obtained, which is dried in vacuo to give 37.0 g of the product as a creamy solid (yield: 82%).
Mp: 208-210 °C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.24 (s, 9 H), 3.89 (s, 3 H), 4.51 (s, 1 H), 6.90 (m, 3 H), 7.23 (d, J = 8.7 Hz, 2 H), 7.63 (s, 1 H), 7.92 (d, J = 8.7 Hz, 2 H).

EXAMPLE 5 4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

[0043]
[0044]

A mixture of N-tert-butyl-4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (37.0 g, 85 mmol, obtained in example 4), concentrated HCl (200 mL) and H₂O (200 mL) is heated at reflux for 3 h. The mixture is allowed to cool and is brought to pH 6 with 6N NaOH. A white precipitate appears, which is collected by filtration and washed with plenty of H₂O and then with CHCl₃. 31 g of the title compound of the example is obtained (yield: 97%), which are recrystallized from acetonitrile.
Mp: 211-212 °C;
¹H-NMR (300 MHz, CDCl₃ + CD₃OD) δ (TMS): 3.90 (s, 3 H), 4.16 (s, CD₃OD + 2 H), 6.93 (m, 3 H), 7.30 (d, J = 8.6 Hz, 2 H), 7.73 (s, 1 H), 7.95 (d, J = 8.7 Hz, 2 H).

References

“European Public Assessment Report: Cimalgex (cimicoxib)”. European Medicines Agency.

23685411	9-1-2013	Detection and quantification of cimicoxib, a novel COX-2 inhibitor, in canine plasma by HPLC with spectrofluorimetric detection: development and validation of a new methodology.	Journal of pharmaceutical and biomedical analysis
23710692	6-1-2013	Efficacy and safety of cimicoxib in the control of perioperative pain in dogs.	The Journal of small animal practice
17335184	4-5-2007	NO-donor COX-2 inhibitors. New nitrooxy-substituted 1,5-diarylimidazoles endowed with COX-2 inhibitory and vasodilator properties.	Journal of medicinal chemistry
15481993	10-21-2004	New water-soluble sulfonylphosphoramidic acid derivatives of the COX-2 selective inhibitor cimicoxib. A novel approach to sulfonamide prodrugs.	Journal of medicinal chemistry
12877584	7-31-2003	Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.	Journal of medicinal chemistry

US2005080084	4-15-2005	Compositions of a cyclooxygenase-2 selective inhibitor and a serotonin-modulating agent for the treatment of central nervous system damage
US2005075341	4-8-2005	Compositions of a cyclooxygenase-2 selective inhibitor and an IKK inhibitor for the treatment of ischemic mediated central nervous system disorders or injury

US2009012307	1-9-2009	Process for the Preparation of 4-(imidazol-1-yl)benzenesulfonamide Derivatives
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Tilmacoxib

July 30, 2014 8:13 am / Leave a comment

Tilmacoxib

JTE-522, JTP-19605, RWJ-57504,

CAS 180200-68-4,

4-(4-Cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide

4-(4-cyclohexyl-2-methyl-1,3-oxazol-5-yl)-2-fluorobenzenesulfonamide

5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo(4,5)imidazo(1,2a)pyridine-4-N–(2-fluorophenyl)carboxamide

4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide

Molecular Formula: C₁₆H₁₉FN₂O₃S

Molecular Weight: 338.397063

Japan Tobacco (JT) (Originator)

Tilmacoxib or JTE-522 is a COX-2 inhibitor and is an effective chemopreventive agent against rat experimental liver fibrosis.^[1]

A member of the class of 1,3-oxazoles that is that is 1,3-oxazole which is substituted at positions 2, 4 and 5 by methyl, cyclohexyl, and 3-fluoro-4-sulfamoylphenyl groups, respectively.

………..

4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: Enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522
J Med Chem 2002, 45(7): 1511

http://pubs.acs.org/doi/abs/10.1021/jm010484p

A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities. In contrast, introduction of a fluorine atom preserved COX-2 potency and notably increased COX1/COX-2 selectivity. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [9d, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.

9d as a white solid: mp 166−167 °C; ¹H NMR (CDCl₃) δ 1.3−1.5 (m, 3H), 1.6−1.9 (m, 7H), 2.51 (s, 3H), 2.79 (tt, J = 3.7, 11.3 Hz, 1H), 5.11 (s, 2H), 7.36−44 (m, 2H), 7.94 (t, J = 7.9 Hz, 1H). Anal. (C₁₆H₁₉FN₂O₃S) C, H, N.

………………

WO 1996019463 OR http://www.google.com/patents/EP0745596A1?cl=en

Example 2

[0080]

Synthesis of 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom)
Step 10) Cyclohexyl 3-fluorobenzyl ketone (formula (IV’); R’=cyclohexyl, R₁‘=3-fluorophenyl)
[0081]

To a solution of tetrakis(triphenylphosphine)palladium (2.00 g) and zinc powder (17.98 g) in 1,2-dimethoxyethane (50 ml) was added a solution of cyclohexanecarbonyl chloride (20.00 g) in 1,2-dimethoxyethane (50 ml) at room temperature under a nitrogen atmosphere. A solution of 3-fluorobenzyl bromide (26.00 g) in 1,2-dimethoxyethane (100 ml) was gradually added dropwise to the mixture with stirring under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, and at room temperature for 2 hours. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. Then, ethyl acetate (200 ml) was added to the residue, and the mixture was washed with 1N hydrochloric acid, and then with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 29.20 g of an oily crude product.
Step 16) 2-Cyclohexyl-1-(3-fluorophenyl)-2-oxoethyl acetate (formula (V”); R’=cyclohexyl, R₁‘=3-fluorophenyl, R₂‘=methyl, Z=oxygen atom)
[0082]

Lead tetraacetate (75.00 g) was added to a solution of the compound (29.20 g) obtained in the above Step 10) in acetic acid (300 ml). The mixture was refluxed under heating for 1.5 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=9:1) to give 18.30 g of the title compound as an oil (yield 50%).
Step 17) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula (XIII); R’=cyclohexyl, R₁‘=3-fluorophenyl, R₂=methyl, Z=oxygen atom)
[0083]

A solution of the compound (18.00 g) obtained in the above Step 16) and ammonium acetate (15.00 g) in acetic acid (100 ml) was refluxed under heating for 5 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 17.20 g of an oily crude product. Step 15) 5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom)
[0084]

To a solution of the compound (17.00 g) obtained in the above Step 17) in chloroform (80 ml) was added dropwise chlorosulfonic acid (27 ml) with stirring under ice-cooling, and the mixture was heated at 100°C for 3 hours. The reaction mixture was cooled to room temperature, and dropwise added to ice-water (300 ml) with stirring. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 20.31 g of a crude product.
[0085]

Aqueous ammonia (28%) was added to a solution of the obtained compound (10.00 g) in tetrahydrofuran (40 ml) with stirring at room temperature, and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was separated and purified by silica gel column chromatography (developing solvent; dichloromethane:ethyl acetate=6:1) to give 5.74 g of the title compound (yield 61%).

Example 2′

[0086]

The compound of Example 2 (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom) was synthesized according to another synthetic method.
Step 11) Cyclohexyl 3-fluorobenzyl ketone oxime (formula (XI); R’= cyclohexyl, R₁‘=3-fluorophenyl)
[0087]

To a solution of the compound (353 g) obtained according to a method similar to that of the above Example 2, Step 10) in ethanol (1300 ml) were added hydroxylamine hydrochloride (123 g) and sodium acetate (158 g). The mixture was refluxed under heating for 2 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was recrystallized from n-heptane to give 160 g of the title compound (yield 42%).
Step 14) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula (XIII); R’=cyclohexyl, R₁‘=3-fluorophenyl, R₂=methyl, Z=oxygen atom)
[0088]

Acetic anhydride (95 ml) was dropwise added to a solution of the compound (158 g) obtained in the above Step 11) in acetic acid (900 ml) with stirring at room temperature, and the mixture was refluxed under heating for 7 hours. The solvent was evaporated under reduced pressure and n-heptane was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution, saturated brine and acetonitrile. The solvent was evaporated under reduced pressure to give 119 g of the title compound as an oil.
[0089]

Then, the obtained compound (119 g) was reacted in the same manner as in the above Example 2, Step 15) to give a compound of Example 2 (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom).

Example 3

[0090]

Synthesis of 4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole (formula (I); R=cyclohexyl, R₁=3-fluoro-4-methylsulfonylphenyl, R₂=methyl, Z=oxygen atom)
Step 15) 4-Cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole (formula (I); R=cyclohexyl, R₁=3-fluoro-4-methylsulfonylphenyl, R₂=methyl, Z=oxygen atom)
[0091]

To a solution of the compound (17.00 g) obtained in the above Example 2, Step 17) in chloroform (80 ml) was dropwise added chlorosulfonic acid (27 ml) with stirring under ice-cooling. The mixture was heated at 100°C for 3 hours. The reaction mixture was cooled to room temperature and dropwise added to ice-water (300 ml) with stirring. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 20.31 g of a crude product.
[0092]

Water (25 ml) was added to the obtained compound (3.66 g). To the mixture were added sodium sulfite (1.42 g) and sodium hydrogencarbonate (1.89 g) successively with stirring at room temperature. The mixture was heated at 70°C for 2 hours. Ethanol (25 ml) and methyl iodide (2.20 g) were added to the mixture, and the mixture was heated at 100°C for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate.
[0093]

The solvent was evaporated under reduced pressure, and the residue was saparated and purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=2:1) to give 0.82 g of the title compound (yield 24%).

References

Yamamoto, H., Kondo, M., Nakamori, S., Nagano, H., Wakasa, K., Sugita, Y., Chang-De, J., Kobayashi, S., Damdinsuren, B., Dono, K., Umeshita, K., Sekimoto, M., Sakon, M., Matsuura, N., Monden, M. (2003). “JTE-522, a cyclooxygenase-2 inhibitor, is an effective chemopreventive agent against rat experimental liver fibrosis1”. Gastroenterology 125 (2): 556–571. doi:10.1016/s0016-5085(03)00904-1. PMID 12891558.

11906292

3-28-2002

4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522(1).

Journal of medicinal chemistry

10406640

7-5-1999

The discovery of rofecoxib, [MK 966, Vioxx, 4-(4′-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2-inhibitor.

Bioorganic & medicinal chemistry letters

Apricoxib, A COX-2 inhibitor.

July 29, 2014 3:52 am / 1 Comment on Apricoxib, A COX-2 inhibitor.

APRICOXIB

A COX-2 inhibitor.

MF; C19H20N2O3S

Mol wt: 356.439

CAS: 197904-84-0

CS-701; TG01, R-109339, TG-01 ,TP-1001
TP-2001, Capoxigem, Kymena, UNII-5X5HB3VZ3Z,

Benzenesulfonamide, 4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]-;

4-[2-(4-Ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide

4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide .

PHASE 2 http://clinicaltrials.gov/search/intervention=Apricoxib

Daiichi Sankyo (innovator)Daiichi Sankyo Co Ltd,

Current developer: Tragara Pharmaceuticals, Inc.

Apricoxib is an orally bioavailable nonsteroidal anti-inflammatory agent (NSAID) with potential antiangiogenic and antineoplastic activities. Apricoxib binds to and inhibits the enzyme cyclooxygenase-2 (COX-2), thereby inhibiting the conversion of arachidonic acid into prostaglandins. Apricoxib-mediated inhibition of COX-2 may induce tumor cell apoptosis and inhibit tumor cell proliferation and tumor angiogenesis. COX-related metabolic pathways may represent crucial regulators of cellular proliferation and angiogenesis.

Chemical structure for apricoxib

R-109339 is a cyclooxygenase-2 (COX-2) inhibitor currently in phase II clinical development at Tragara Pharmaceuticals for the oral treatment of non-small cell lung cancer (NSCLC) and for the treatment of inflammation. Additional phase II clinical trials are ongoing in combination with gemcitabine and erlotinib for the treatment of pancreas cancer. The company had been evaluating R-109339 for the treatment of colorectal cancer, but development for this indication was discontinued for undisclosed reasons. Daiichi Sankyo and Tragara Pharmaceuticals had been conducting phase II clinical trials with the drug candidate for the oral treatment of arthritis and for the treatment of breast cancer, respectively; however, no recent development for this indication has been reported.

COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid, which is derived from the cellular phospholipid bilayer by phospholipase A2. In addition to several other functions, prostaglandins act as messenger molecules in the process of inflammation. The compound is also designed to act against a well-defined cancer pathway that affects several routes of cancer pathogenesis. In preclinical cancer models, R-109339 demonstrated superiority to compounds with similar mechanisms of action and potential for use in combination with cisplatin. Furthermore, the compound demonstrated the ability to inhibit the cachexia and weight loss seen in mouse tumor models.

Apricoxib, (CS-706, 1) 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, a small-molecule, orally active, selective COX-2 inhibitor was discovered by investigators at Daiichi Sankyo in 1996. Clinical studies demonstrated potent analgesic activity and preclinical studies demonstrated good pharmacokinetics, pharmacodynamics and gastrointestinal tolerability. As an anticancer agent, preclinical studies demonstrated efficacy in biliary tract cancer models and colorectal carcinoma, and Recamp et al.

The original synthetic route is outlined below. Though the initial two steps were accomplished with decent yields, the final step of pyrrolidine formation followed by dehydration and dehydrocyanation produced only 3% of 1 as a brown powder. The yield in the last step of the synthesis of the 2-(4-methoxyphenyl) analog, 2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, was 6%, indicating that this synthesis route is problematic.

14 Kimura T, Noguchi Y, Nakao A, Suzuki K, Ushiyama S, Kawara A, Miyamoto M. 799823. EP. 1997:A1.

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……………………….

Synthesis

Bioorg Med Chem Lett. Oct 15, 2011; 21(20): 6071–6073.

Published online Aug 19, 2011. doi: 10.1016/j.bmcl.2011.08.050

SEE AT

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310163/

An efficient synthesis of apricoxib (CS-706), a selective cyclooxygenase inhibitor, was developed using copper catalysed homoallylic ketone formation from methyl 4-ethoxybenzoate followed by ozonolysis to an aldehyde, and condensation with sulphanilamide. This method provided multi-gram access of aprocoxib in good yield. Apricoxib exhibited potency equal to celecoxib at inhibition of prostaglandin E₂ synthesis in two inflammatory breast cancer cell lines.

We envisioned that 7 could be prepared by ozonolysis of homoallylic ketone (8) (Route B). A recent development in the synthesis of homoallylic ketones by Dorr et al. via copper-catalyzed cascade addition of alkenylmagnesium bromide to an ester a²⁴ was examined. Treatment of commercially available methyl 4-ethoxybenzoate with 1-propenylmagnesium bromide (4.0 equiv) in presence of CuCN (0.6 equiv) resulted in 95% yield of desired ketone8 after silica gel chromatography, along with a minor amount of unreacted ester).b²⁵

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Efficient synthesis of apricoxib (1):

The product was a mixture of cis/trans R/S stereoisomers, as detected in the ¹H NMR spectrum, and was used directly in the next step without separation. Ozone was bubbled through a solution of 8 in MeOH/CH₂Cl₂ at −78°C, until all starting materials were consumed. The ozonide was then reduced to aldehyde 7 by treatment with Me₂S overnight. Removal of volatiles and subsequent addition and evaporation of toluene gave the crude 1,4-dicarbonyl compound 7 which was sufficiently pure for the following condensation step. The ¹H NMR signal at 9.78 ppm of the crude product confirmed the formation of the aldehyde. No attempt was made to characterize the enantiomeric ratio of 7 since the dehydration/aromatization reaction of the next step removes the chirality of the product. Treatment of 7 with sulfanilamide in 40% acetic acid-acetonitrile at 70°C for three hours resulted in a brown product. Purification by silica gel flash chromatography yielded 71% of pure 1 as a white solid.c²⁶

a24. Dorr AA, Lubell WD. Can J Chem. 2007;85:1006.

b25. Synthesis of 1-(4-ethoxy-phenyl)-3-methyl-hex-4-en-1-one (8): To a stirred suspension of CuCN (1.8 g, 20.0 mmol) in 50 mL of dry THF at −78°C under argon, a solution of 1-propenylmagnesium bromide (133.2 mmol, 265 mL of 0.5 M solution in THF) was added dropwise. The slurry was stirred for an additional 30 min and then a solution of methyl 4-ethoxybenzoate (6.0 g, 33.3 mmol) in 60 mL of dry THF was added slowly. The stirred reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with ice cold saturated aqueous NaH₂PO₄ (100mL) and the mixture was extracted with ether (4 × 100 mL). The combined ether extracts were washed with brine (2 × 100mL), dried (MgSO₄), filtered, and evaporated to dryness. The crude homoallylic ketone was purified by silica gel flash chromatography using a gradient of ethyl acetate in hexane as the eluent to give 8 (7.4 g, 95%) as a colorless oil. ¹H NMR (CDCl₃, 300.0 MHz) δ 1.04–1.07 (m, 3H), 1.44 (t, J = 6.9 Hz, 3H), 1.6–1.64 (m, 3H), 2.8–2.96 (m, 2.5H), 3.2 (m, 0.5H), 4.1 (q, J = 6.9 Hz, 2H), 5.25 (m, 0.5 H), 5.34–5.46 (m, 1.5H), 6.92 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H). ¹³C NMR (CDCl₃, 75.0 MHz) δ 12.9, 14.6, 17.9, 20.4, 21.0, 28.4, 33.0, 45.4, 45.5, 63.7, 114.1, 123.1, 123.4, 130.2, 130.3, 135.5, 136.0, 141.9, 162.7, 198.1. M+H Calcd: 233.1542; Found, 233.2482.

c26. Synthesis of Apricoxib (1): Homoallylic ketone (8) (5.0 g, 21.53 mmol) in 180 mL of CH₂Cl₂/MeOH (1:5) was treated with ozone bubbles at −78°C until a blue coloration persisted. The solution was purged with argon, 8.0 mL of dimethylsulphide (21.5 mmol) was added, and the reaction mixture then warmed slowly to rt overnight. The solvent was evaporated under vacuum to give 7 which was then diluted with 100 mL of 40 % acetic acid in acetonitrile, (v/v) and sulphanilamide (4.0 g, 23.2 mmol) was added. The mixture was refluxed until complete consumption of 1,4-dicarbonyl compound was detected by TLC (ca 3 h). After cooling to room temperature, the product was concentrated under vacuum and diluted with 250 mL of ethyl acetate. The organic layer then washed with saturated Na₂CO₃ solution (3 × 50 mL) followed by brine (1 × 50 mL), dried (MgSO₄), and evaporated to dryness. The crude brown material was purified by silica gel flash chromatography using a gradient of EtOAc in hexane to give apricoxib as white solid (5.5 g, 15.43 mmol, 71%).

m.p. 161–163°C (lit. 135–139°C¹⁴).

¹H NMR (CDCl₃, 300.0 MHz) δ 1.32 (t, J = 6.9 Hz, 3H), 2.1 (s, 3H), 3.92 (q, J = 6.9 Hz, 2H), 4.95 (s, 2H), 6.14 (m, 1H), 6.63 (m, 1H), 6.69 (d, J = 6.6 Hz, 2H), 6.94 (d, J = 6.6 Hz, 2H), 7.13 (d, J = 6.6 Hz, 2H), 7.74 (d, J= 6.6 Hz, 2H).

¹³C NMR (CDCl₃, 75.0 MHz) δ 11.7, 14.8, 63.4, 82.4, 113.2, 114.4, 121.0, 121.1, 124.9, 125.2, 127.4, 129.7, 133.6, 138.7, 144.2, 158.0

M+H Calcd: 357.1273; Found, 357.1252.

01

Click here to view.^{(2.1M, pdf) DOWNLOAD TO GET NMR , 13C, COSY}

Supplementary Material

¹H, ¹³C, and COSY NMR spectra of compounds 1 and 8.

……………

SYNTHESIS

synthesis

In one strategy, bromination of 4-ethoxyacetophenone (I) with Br2 yields 2-bromo-1-(4-ethoxyphenyl)ethanone (II) along with the byproduct 2-bromo-1-(3-bromo-4-ethoxyphenyl)ethanone, which are separated using HPLC. Alkylation of propionaldehyde N,Ndiisobutylenamine (III) with bromo ketone (II) and subsequent ketalization with neopentyl glycol (IV) using p-TsOH·H2O and, optionally, H2SO4 in MeCN gives monoprotected ketoaldehyde (V) (1). Finally, cyclization of ketoaldehyde derivative (V) with 4-aminobenzenesulfonamide (VI) in the presence of AcOH in PrOH/H2O at 90-100 °C furnishes apricoxib

Intermediate (V) can also be prepared by reaction of 1-(4- ethoxyphenyl)-2-buten-1-one (VII) with CH3NO2 in the presence of DBU in THF to produce nitro ketone (VIII). Subsequent treatment of nitroderivative (VIII) with neopentyl glycol (IV) and NaOMe and MeOH gives acetal (V) (2).In an alternativestrategy, condensation of 4-ethoxyacetaldehyde (IX) with 4-sulfamoylaniline (VI) in refluxing EtOH furnishesN-(4-ethoxybenzylidene)-

4-sulfamoylaniline (X), which then condenses with trimethylsilyl cyanide (XI) in the presence of ZnCl2 in THF yielding α- amino nitrile (XII). Cyclization of this compound with methacrolein (XIII) using LiHMDS in THF affords apricoxib

reference for above

Drugs of the Future 2011, 36(7): 503-509
Kojima, S., Ooyama, J. (Daiichi Sankyo Co., Ltd.). Process for production of brominated acetophenone. WO 2008020617.
Fujimoto, K., Takebayashi, T., Noguchi, Y., Saitou, T. (Daiichi Sankyo Co., Ltd.). Production of 4-methyl-1,2-diarylpyrrole and intermediate for synthesizing the same. JP 2000080078
Kimura, T., Noguchi, Y., Nakao, A., Suzuki, K., Ushiyama, S., Kawara, A., Miyamoto, M. (Daiichi Sankyo Co., Ltd.). 1,2-Diphenylpyrrole derivatives,their preparation and their therapeutic uses. CA 2201812, EP 0799823, JP 1997823971, US 5908858.

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15. Moberly, James B.; Xu, Jianbo; Desjardins, Paul J.; Daniels, Stephen E.; Bandy, Donald P.; Lawson, Janet E.; Link, Allison J.; Truitt, Kenneth E. A randomized, double-blind, celecoxib- and placebo-controlled study of the effectiveness of CS-706 in acute postoperative dental pain. Clinical Therapeutics (2007), 29(3), 399-412.
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18. Oitate, Masataka; Hirota, Takashi; Koyama, Kumiko; Inoue, Shin-ichi; Kawai, Kenji; Ikeda, Toshihiko. Covalent binding of radioactivity from [14C] rofecoxib, but not [14C] celecoxib or [14C] CS-706, to the arterial elastin of rats. Drug Metabolism and Disposition (2006), 34(8), 1417-1422.

19. Kastrissios, H.; Rohatagi, S.; Moberly, J.; Truitt, K.; Gao, Y.; Wada, R.; Takahashi, M.; Kawabata, K.; Salazar, D. Development of a predictive pharmacokinetics model for a novel cyclooxygenase-2 inhibitor. Journal of Clinical Pharmacology (2006), 46(5), 537-548. CODEN: JCPCBR ISSN:0091-2700. CAN 145:327959 AN 2006:479516

20. Denis, Louis J.; Compton, Linda D. Method using camptothecin compounds, pyrimidine derivatives, and antitumor agents for treating abnormal cell growth. U.S. Pat. Appl. Publ. (2005), 32 pp. CODEN: USXXCO US 2005272755 A1 20051208 CAN 144:17160 AN 2005:1294044

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22. Di Salle, Enrico; Piscitelli, Gabriella; Massimini, Giorgio; Purandare, Dinesh; Dekoning, Gans Hendrik. Combined method for treating hormone-dependent disorders with aromatase inactivator exemestane and other therapeutic agents. PCT Int. Appl. (2002), 49 pp. CODEN: PIXXD2 WO 2002072106 A2 20020919 CAN 137:226651 AN 2002:716096

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24. McKearn, John P.; Gordon, Gary; Cunningham, James J.; Gately, Stephen T.; Koki, Alane T.; Masferrer, Jaime L. Method of using a cyclooxygenase-2 inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia. PCT Int. Appl. (2000), 236 pp. CODEN: PIXXD2 WO 2000038730 A2 20000706 CAN 133:84243 AN 2000:456927

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Golden Root (Rhodiola rosea)…….a queen of adaptogenic herbs

July 28, 2014 11:27 am / Leave a comment

Golden Root (Rhodiola rosea) – Also called Arctic Root or Roseroot, golden root is considered a queen of adaptogenic herbs. As one blogger puts it, “[Golden root] allows us to regulate our immune, physiological and neurological responses to stress, allowing us to survive not only rough environmental/weather challenges, but also to adapt and adjust our often neurotic mental habits and crazy social/political climates as well.

”The Russians use it to improve physical stamina and adapt to environmental stress. In Siberia, people still say, “Those who drink Rhodiola tea will live more than 100 years old.” The extract possesses positive mood enhancing and anti-stress properties with no detectable levels of toxicity. Golden root works by enhancing the body’s ability to make serotonin, dopamine, and other neurotransmitters that aid in happiness and stress-reduction.

Rhodiola rosea (commonly golden root, rose root, roseroot, Aaron’s rod, arctic root, king’s crown, lignum rhodium, orpin rose) is a perennial flowering plant in the family Crassulaceae. It grows in cold regions of the world, including much of the Arctic, the mountains ofCentral Asia, scattered in eastern North America from Baffin Island to the mountains of North Carolina, and mountainous parts of Europe, such as the Alps, Pyrenees, and Carpathian Mountains, Scandinavia, Iceland, Great Britain and Ireland. It grows on sea cliffs and on mountains^[2] at altitudes up to 2280 meters.^[where?]^{[citation needed]} Several shoots grow from the same thick root. Shoots may reach 5 to 35 cm in height. R. rosea is dioecious – having separate female and male plants.

History

The first time that R. rosea is described was from Dioscorides in De Materia Medica.

Uses

Plant

Some studies have found support for it having antidepressant effects.^[3]^[4] It is not approved by the U.S. Food and Drug Administration (FDA) to cure, treat, or prevent any disease. In fact, the FDA has forcibly removed some products containing R. rosea from the market due to disputed claims that it treats cancer, anxiety, influenza, the common cold, bacterial infections, and migraines.^[5]

R. rosea may be effective for improving mood and alleviating depression. Pilot studies on human subjects^[6]^[7]^[8] showed it improves physical and mental performance, and may reduce fatigue.

In Russia and Scandinavia, R. rosea has been used for centuries to cope with the cold Siberianclimate and stressful life.^{[citation needed]}^[9]^[10] Such effects were provided with evidence in laboratory models of stress using the nematode C. elegans,^[11] and in rats in which Rhodiola effectively prevented stress-induced changes in appetite, physical activity, weight gain and the estrus cycle.^[12]

The plant has been used in traditional Chinese medicine, where it is called hóng jǐng tiān (红景天). The medicine can be used to prevent altitude sickness.^{[citation needed]}

The aerial portion is consumed as food in some parts of the world, sometimes added to salads.^[13]

Phytochemicals and potential health effects

Withering flower

Scientists have identified about 140 chemical compounds in the subterranean portions of R. rosea.^[14] Rhodiola roots contain phenols,rosavin, rosin, rosarin, organic acids, terpenoids, phenolcarbonic acids and their derivatives, flavonoids, anthraquinones, and alkaloids.

The chemical composition of the essential oil from R. rosea root growing in different countries varies. For example, rosavin, rosarin and rosin at their highest concentration according to many tests can be found only in R. rosea of Russian origin; the main component of the essential oil from Rhodiola growing in Bulgaria are geraniol and myrtenol; in China the main components are geraniol and 1-octanol; and in India the main component is phenylethilic alcohol. Cinnamic alcohol was discovered only in the sample from Bulgaria.^[15]

R. rosea contains a variety of compounds that may contribute to its effects,^[16] including the class of rosavins that includes rosavin, rosarin, and rosin. Several studies have suggested that the most active components are likely to be rhodioloside and tyrosol,^[17] with other components being inactive when administered alone, but showing synergistic effects when a fixed combination of rhodioloside, rosavin, rosarin and rosin was used.^[18] Authentication, as well as potency, of R. rosea crude material and standardized extracts thereof are carried out with validated high-performance liquid chromatography analyses to verify the content of the marker constituents salidroside, rosarin, rosavin, rosin and rosiridin.^[19]

Although rosavin, rosarin, rosin and salidroside (and sometimes p-tyrosol, rhodioniside, rhodiolin and rosiridin) are among suspected active ingredients of R. rosea, these compounds are mostly polyphenols. There is no evidence that these chemicals have any physiological effect in humans that could prevent or reduce risk of disease.^[20]

Although these phytochemicals are typically mentioned as specific to Rhodiola extracts, there are many other constituent phenolic antioxidants, including proanthocyanidins,quercetin, gallic acid, chlorogenic acid and kaempferol.^[21]^[22]

Dried R. rosea root

Animal tests have suggested a variety of beneficial effects for R. rosea extracts,^[23] and there is some scientific evidence for its efficacy as a treatment for depression and fatigue ^[6]^[7]^[24]^[25] in humans.

Scientific evidence

R. rosea extract exerts an antifatigue effect that increases mental performance, particularly the ability to concentrate in healthy subjects^[6]^[7]^[24] and burnout patients with fatigue syndrome.^[25] Rhodiola significantly reduced symptoms of fatigue and improved attention after four weeks of repeated administration.^[25] A 2007 clinical trial from Armenia showed significant effect for a Rhodiola extract in doses of 340–680 mg per day in male and female patients from 18 to 70 years old with mild to moderate depression. No side effects were demonstrated at these doses.^[3] One study found inhibition of MAO-A and MAO-B.^[26] Studies on whether Rhodiola improves physical performance have been inconclusive, with some studies showing some benefit,^[27] while others show no significant difference.^[28]

Two systematic reviews on R. rosea extracts concluded that the research evidence is contradictory, and definite conclusions over its efficacy to relieve mental and physical fatigue are hampered by the lack of rigorously-designed, well-controlled randomized control trials ^[29]

In clinical medical trials on people R. rosea extract has a positive effect on sensitive and fading skin improving overall skin condition.^[30]^{[full citation needed]}

R. rosea promotes the release of norepinephrine from rat pineal corpus cavernosum smooth muscle cell and artery endothelium cell, which was correlated with its effect of resisting senility.^[31] R. rosea extract has been found to increase the life span of fruit fly (Drosophila) by 24% independently of dietary restriction.^[32]

R. rosea may enhance the detoxification of many toxic heavy metals.^[33]

References

Jump up^ “Rhodiola rosea – Plants For A Future database report”. http://www.pfaf.org. Retrieved 2008-02-23.
Jump up^ Stace, C.A. (2010). New flora of the British isles (Third ed.). Cambridge, U.K.: Cambridge University Press. p. 138. ISBN 9780521707725.
^ Jump up to:^a ^b Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmström C, Panossian A (2007). “Clinical trial of Rhodiola rosea L. extract in the treatment of mild to moderate depression”. Nord J Psychiatry 61 (5): 343–8. doi:10.1080/08039480701643290.PMID 17990195.
Jump up^ Dwyer AV, Whitten DL, Hawrelak JA (March 2011). “Herbal medicines, other than St. John’s Wort, in the treatment of depression: a systematic review” (PDF). Altern Med Rev 16 (1): 40–9. PMID 21438645.
Jump up^ See for example, Letter, dated April 21, 2005, Food and Drug Administration
^ Jump up to:^a ^b ^c Shevtsov VA, Zholus BI, Shervarly VI, et al. (Mar 2003). “A randomized trial of two different doses of Rhodiola rosea extract versus placebo and control of capacity for mental work”. Phytomedicine 10 (2–3): 95–105. doi:10.1078/094471103321659780.PMID 12725561.
^ Jump up to:^a ^b ^c Darbinyan V, Kteyan A, Panossian A, Gabrielian E, Wikman G, Wagner H (Oct 2000). “Rhodiola rosea in stress induced fatigue—a double blind cross-over study of a standardized extract with a repeated low-dose regimen on the mental performance of healthy physicians during night duty”. Phytomedicine 7 (5): 365–71. doi:10.1016/S0944-7113(00)80055-0. PMID 11081987.
Jump up^ Ha Z, Zhu Y, Zhang X, et al. (Sep 2002). “[The effect of rhodiola and acetazolamide on the sleep architecture and blood oxygen saturation in men living at high altitude]”.Zhonghua Jie He He Hu Xi Za Zhi (in Chinese) 25 (9): 527–30. PMID 12423559.
Jump up^ Azizov, AP; Seĭfulla, RD (May–Jun 1998). “[The effect of elton, leveton, fitoton and adapton on the work capacity of experimental animals].”. Eksperimental’naia i klinicheskaia farmakologiia 61 (3): 61–3. PMID 9690082.
Jump up^ Darbinyan, V; Kteyan, A; Panossian, A; Gabrielian, E; Wikman, G; Wagner, H (Oct 2000). “Rhodiola rosea in stress induced fatigue–a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty.”. Phytomedicine : international journal of phytotherapy and phytopharmacology 7 (5): 365–71. doi:10.1016/S0944-7113(00)80055-0. PMID 11081987.
Jump up^ Wiegant FA, Surinova S, Ytsma E, Langelaar-Makkinje M, Wikman G, Post JA (Jun 2008). “Plant adaptogens increase lifespan and stress resistance in C. elegans”.Biogerontology 10 (1): 27–42. doi:10.1007/s10522-008-9151-9. PMID 18536978.
Jump up^ Mattioli L, Funari C, Perfumi M (May 2008). “Effects of Rhodiola rosea L. extract on behavioural and physiological alterations induced by chronic mild stress in female rats”.Journal of Psychopharmacology (Oxford) 23 (2): 130–42.doi:10.1177/0269881108089872. PMID 18515456.
Jump up^ Saratikov A.S. (1974). Golden Root (Rhodiola Rosea) (2nd ed.). Publishing House of Tomsk University. p. 158.
Jump up^ Panossian, A., Wikman, G. (2010). “Rosenroot (Roseroot): Traditional Use, Chemical Composition, Pharmacology, and Clinical Efficacy”. Phytomedicine 17 (5-6): 481–493.doi:10.1016/j.phymed.2010.02.002.
Jump up^ Evstavieva L., Todorova M., Antonova D., Staneva J. (2010). “Chemical composition of the essential oils of Rhodiola rosea L. of three different origins”. Pharmacogn Mag. 6 (24): 256–258.
Jump up^ Kucinskaite A, Briedis V, Savickas A (2004). “[Experimental analysis of therapeutic properties of Rhodiola rosea L. and its possible application in medicine]”. Medicina (Kaunas) (in Lithuanian) 40 (7): 614–9. PMID 15252224.
Jump up^ Mao Y, Li Y, Yao N (Nov 2007). “Simultaneous determination of salidroside and tyrosol in extracts of Rhodiola L. by microwave assisted extraction and high-performance liquid chromatography”. J Pharm Biomed Anal 45 (3): 510–5. doi:10.1016/j.jpba.2007.05.031.PMID 17628386.
Jump up^ Panossian A, Nikoyan N, Ohanyan N, et al. (Jan 2008). “Comparative study of Rhodiola preparations on behavioral despair of rats”. Phytomedicine 15 (1–2): 84–91.doi:10.1016/j.phymed.2007.10.003. PMID 18054474.
Jump up^ Ganzera M, Yayla Y, Khan IA (April 2001). “Analysis of the marker compounds of Rhodiola rosea L. (golden root) by reversed phase high performance liquid chromatography”. Chem. Pharm. Bull. 49 (4): 465–7. doi:10.1248/cpb.49.465.PMID 11310675.
Jump up^ Boudet AM (2007). “Evolution and current status of research in phenolic compounds”.Phytochemistry 68 (22–24): 2722–35. doi:10.1016/j.phytochem.2007.06.012.PMID 17643453.
Jump up^ Yousef GG, Grace MH, Cheng DM, Belolipov IV, Raskin I, Lila MA (Nov 2006). “Comparative phytochemical characterization of three Rhodiola species”. Phytochemistry67 (21): 2380–91. doi:10.1016/j.phytochem.2006.07.026. PMID 16956631.
Jump up^ Liu Q, Liu ZL, Tian X (Feb 2008). “[Phenolic components from Rhodiola dumulosa]”.Zhongguo Zhong Yao Za Zhi (in Chinese) 33 (4): 411–3. PMID 18533499.
Jump up^ Perfumi M, Mattioli L (Jan 2007). “Adaptogenic and central nervous system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice”.Phytother Res 21 (1): 37–43. doi:10.1002/ptr.2013. PMID 17072830.
^ Jump up to:^a ^b Spasov. A.A., Mandrikov, V.B., Mitonova, I.A., 2000b. The effect of Dhodaxonon psycho-physiologic and physical adaptation of students to the academic load. Experimental and Clinical Pharmacology 63 (1), 76-78.
^ Jump up to:^a ^b ^c Olsson E.M.G., von Schéele B., Panossian A.G. (2009). “A randomized double-blind placebo controlled parallel group study of an extract of Rhodiola rosea roots as treatment for patients with stress related fatigue”. Planta medica 75 (2): 105–112.doi:10.1055/s-0028-1088346. PMID 19016404.
Jump up^ van Diermen, D.; Marston, A.; Bravo, J.; Reist, M.; Carrupt, PA.; Hostettmann, K. (Mar 2009). “Monoamine oxidase inhibition by Rhodiola rosea L. roots.”. J Ethnopharmacol122 (2): 397–401. doi:10.1016/j.jep.2009.01.007. PMID 19168123.
Jump up^ De Bock K, Eijnde BO, Ramaekers M, Hespel P (Jun 2004). “Acute Rhodiola rosea intake can improve endurance exercise performance”. Int J Sport Nutr Exerc Metab 14(3): 298–307. PMID 15256690.
Jump up^ Walker TB, Altobelli SA, Caprihan A, Robergs RA (Aug 2007). “Failure of Rhodiola rosea to alter skeletal muscle phosphate kinetics in trained men”. Metab Clin Exp. 56(8): 1111–7. doi:10.1016/j.metabol.2007.04.004. PMID 17618958.
Jump up^ Ishaque, Sana; Shamseer, Larrisa; Bukutu, Cecilia; Vohra, Sunita. “Rhodiola rosea for physical and mental fatigue: a systematic review”. BMC Complementary and Alternative Medicine 12 (1): 70. doi:10.1186/1472-6882-12-70. PMID 3541197.
Jump up^ Diemant et al., 2008
Jump up^ Effect of Rodiola on level of NO and NOS in cultured rats penile corpus cavernosum smooth muscle cell and artery endothelium cell Kong X., Shi F., Chen Y., Lu H., Yao M., Hu M. Chinese Journal of Andrology 2007 21:10 (6-11)
Jump up^ Schriner, Samuel E.; Lee, Kevin; Truong, Stephanie; Salvadora, Kathyrn T.; Maler, Steven; Nam, Alexander; Lee, Thomas; Jafari, Mahtab; Englert, Christoph (21 May 2013). “Extension of Drosophila Lifespan by Rhodiola rosea through a Mechanism Independent from Dietary Restriction”. PLoS ONE 8 (5): e63886. doi:10.1371/journal.pone.0063886.
Jump up^ Boon-Niermeijer, E.K.; van den Berg, A.; Wikman, G.; Wiegant, F.A.C. “Phyto-adaptogens protect against environmental stress-induced death of embryos from the freshwater snail Lymnaea stagnalis”. Phytomedicine 7 (5): 389–399. doi:10.1016/S0944-7113(00)80060-4.

External links

Media related to Rhodiola rosea at Wikimedia Commons
Whole Health MD, Reference Library
Plants For A Future, Rhodiola rosea Rose Root PFAF
Wilderness Medical Society, Lack of Effect of Rhodiola on Hypoxemia and Oxidative Stress

Tiny amounts of BPA can alter mammary gland development

July 28, 2014 2:09 am / Leave a comment

CLINICALNEWS.ORG

Researchers see BPA effects in monkey mammary glands

Study adds to growing health concerns about common plastic additive

PULLMAN, Wash.—A new study finds that fetal exposure to the plastic additive bisphenol A, or BPA, alters mammary gland development in primates. The finding adds to the evidence that the chemical can be causing health problems in humans and bolsters concerns about it contributing to breast cancer.

“Previous studies in mice have demonstrated that low doses of BPA alter the developing mammary gland and that these subtle changes increase the risk of cancer in the adult,” says Patricia Hunt, a geneticist in Washington State University’s School of Molecular Biosciences. “Some have questioned the relevance of these findings in mice to humans. But finding the same thing in a primate model really hits uncomfortably close to home.”

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Mom will teach you NMR

July 26, 2014 11:38 am / Leave a comment

Dedicated to all moms in the world

ETHYL PROPIONATE NMR, carbonyl is dad and oxygen mom, a methyl gets more attention

ORIGINALLY IN http://orgspectroscopyint.blogspot.in/2014/07/ethyl-propionate-nmr-carbonyl-is-dad.html

C=O group is dad

O atom is mom

Carbonyl is dad and oxygen mom hence c labelled methyl has higher chemical shift and gets a little more attention

SEE BELOW

NMR IS EASY

A chemical has Formula: C₅H₁₀O₂

C₅H₁₀O₂
Rule 2, omit O, gives C₅H₁₀
5 – 10/2 + 1 = 1 degree of unsaturation.
Look for 1 pi bond or aliphatic ring.

The band at 1740 indicates a carbonyl, probably a saturated aliphatic ester. The bands at 3000-2850 indicate C-H alkane stretches. The bands in the region 1320-1000 could be due to C-O stretch, consistent with an ester.

Structure answer

This is the structure. See if you can assign the peaks on your own.

NMR answer

C has a higher chemical shift than D because it’s closer to a more electron-withdrawing functional group.

Carbonyl is dad and oxygen mom, hence c has higher chemical shift and gets a little more attention in proton nmr

13 C NMR

Mass spectrum

RAMAN

WHAT HAPPENS WHEN A CHLORO IS INTRODUCED

THE INTERPRETATION IS BELOW

remember “a” labelled CH3 appears as a doublet

WHEN THERE IS ONE METHYL

WHEN THERE ONE CH2 SHORT

WHEN MOM HAS ONE MORE CH2

PROPYL PROPIONATE, try this on your own

1H NMR

see interpretation

BIGGER ONE THAN OBOVE

13C NMR

APT

COSY

WILL PASTE INTERPRETATION AFTER ONE WEEK……………….

Natural products from plants protect skin during cancer radiotherapy

July 26, 2014 3:15 am / Leave a comment

CLINICALNEWS.ORG

PUBLIC RELEASE DATE:

24-Jul-2014
Radiotherapy for cancer involves exposing the patient or their tumor more directly to ionizing radiation, such as gamma rays or X-rays. The radiation damages the cancer cells irreparably. Unfortunately, such radiation is also harmful to healthy tissue, particularly the skin over the site of the tumor, which is then at risk of hair loss, dermatological problems and even skin cancer. As such finding ways to protect the overlying skin are keenly sought.

Writing in the International Journal of Low Radiation, Faruck Lukmanul Hakkim of the University of Nizwa, Oman and Nagasaki University, Nagasaki, Japan, and colleagues there and at Macquarie University, New South Wales, Australia, Bharathiar University, India and Konkuk University, South Korea, explain how three ubiquitous and well-studied natural products derived from plants can protect the skin against gamma radiation during radiotherapy.

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Sage Therapeutics receives fast track designation for status epilepticus therapy

July 24, 2014 7:34 am / 1 Comment on Sage Therapeutics receives fast track designation for status epilepticus therapy

SAGE-547

ALLOPREGNANOLONE

Sage Therapeutics (Originator)

Sage Therapeutics

For Epilepsy, status epilepticus

SGE-102; SAGE-547; allopregnanolone; allosteric GABA A receptor modulators (CNS disorders),

Sage Therapeutics receives fast track designation for status epilepticus therapy
Ligand Pharmaceuticals announced that its partner Sage Therapeutics has received fast track designation from the US Food and Drug Administration (FDA) for the Captisol-enabled SAGE-547 to treat status epilepticus.

read at

http://www.pharmaceutical-technology.com/news/newssage-therapeutics-receives-fast-track-designation-for-status-epilepticus-therapy-4324543?WT.mc_id=DN_News

Chemical Name: (3α)-Allopregnanolone

Synonyms: (+)-3α-Hydroxy-5α-pregnan-20-one; (3α,5α)-3-Hydroxypregnan-20-one; 3α,5α-THP; 3α,5α-Tetrahydroprogesterone; 3α-Hydroxy-5α-dihydroprogesterone; 3α-Hydroxy-5α-pregnan-20-one; 3α-Hydroxy-5α-pregnane-20-one; 5α-Pregnan-3α-ol-20-one; 5α-Pregnane-3α-ol-20-one; Allopregnan-3α-ol-20-one; Allopregnanolone; Allotetrahydroprogesterone;

CAS Number: 516-54-1

Applications: (3α)-Allopregnanolone acts as a GABAA receptor positive allosteric modulator. (3α)-Allopregnanolone is a metabolite of Progesterone (P755900). (3α)-Allopregnanolone is a neuroactive steroid present in the blood and also the brain.

References: Puja, G. et al.: Neuron, 4, 759 (1990); Belelli, D. et ael. Neurosteroid, 6, 565 (2006); Viapiano, M. et al.: Neurochem. Res., 23, 155 (1998);

Mol. Formula: C21H34O2

Appearance: White Solid

Melting Point: 174-176°C

Mol. Weight: 318.49

SAGE-547 is a GABA(A) receptor modulator in phase I/II clinical trials at Sage Therapeutics as adjunctive therapy for the treatment of adults with super-refractory status epilepticus (SRSE).

In 2014, orphan drug designation was assigned in the U.S for the treatment of status epilepticus. In July 2014, fast track designation was received in the U.S. for the treatment of adults with super-refractory status epilepticus (SRSE).

July 22, 2014

SAGE Therapeutics, a biopharmaceutical company developing novel medicines to treat life-threatening, rare central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has granted fast track designation to the SAGE-547 development program. SAGE-547 is an allosteric modulator of GABAA receptors in development for the treatment of adult patients with refractory status epilepticus who have not responded to standard regimens (super-refractory status epilepticus, or SRSE). SAGE is currently evaluating SAGE-547 in a Phase 1/2 clinical trial for the treatment of SRSE. Preliminary data indicate that the first four patients enrolled in the clinical trial met the key efficacy endpoint, in that each was successfully weaned off his or her anesthetic agent while SAGE-547 was being administered. There have also been no reported drug-related serious adverse events in these four patients to date.

“The fast track designation for SAGE-547 recognizes the significant unmet need that exists in the treatment of super-refractory status epilepticus,” said Jeff Jonas, MD, chief executive officer of SAGE Therapeutics. “The receipt of orphan drug designation earlier this year for status epilepticus and the fast track designation are both significant regulatory milestones for SAGE-547, and we will continue to work closely with the FDA to advance our lead compound and the additional programs in our pipeline for the treatment of life-threatening CNS disorders.”

Fast track designation is granted by the FDA to facilitate the development and expedite the review of drug candidates that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

About SAGE-547

SAGE-547 is an allosteric modulator of both synaptic and extra-synaptic GABAA receptors. GABAA receptors are widely regarded as validated drug targets for a variety of CNS disorders, with decades of research and multiple approved drugs targeting these receptor systems. SAGE-547 is an intravenous agent in Phase 1/2 clinical development as an adjunctive therapy, a therapy combined with current therapeutic approaches, for the treatment of SRSE.

About Status Epilepticus (SE)

SE is a life-threatening seizure condition that occurs in approximately 150,000 people each year in the U.S., of which 30,000 SE patients die.1 We estimate that there are 35,000 patients with SE in the U.S. that are hospitalized in the intensive care unit (ICU) each year. An SE patient is first treated with benzodiazepines, and if no response, is then treated with other, second-line, anti-seizure drugs. If the seizure persists after the second-line therapy, the patient is diagnosed as having refractory SE (RSE), admitted to the ICU and placed into a medically induced coma. Currently, there are no therapies that have been specifically approved for RSE; however, physicians typically use anesthetic agents to induce the coma and stop the seizure immediately. After a period of 24 hours, an attempt is made to wean the patient from the anesthetic agents to evaluate whether or not the seizure condition has resolved. Unfortunately, not all patients respond to weaning attempts, in which case the patient must be maintained in the medically induced coma. At this point, the patient is diagnosed as having SRSE. Currently, there are no therapies specifically approved for SRSE.

About SAGE Therapeutics

SAGE Therapeutics (NASDAQ: SAGE) is a biopharmaceutical company committed to developing and commercializing novel medicines to treat life-threatening, rare CNS disorders. SAGE’s lead program, SAGE-547, is in clinical development for super-refractory status epilepticus and is the first of several compounds the company is developing in its portfolio of potential seizure medicines. SAGE’s proprietary chemistry platform has generated multiple new compounds that target GABAA and NMDA receptors, which are broadly accepted as impacting many psychiatric and neurological disorders. SAGE Therapeutics is a public company launched in 2010 by an experienced team of R&D leaders, CNS experts and investors. For more information, please visitwww.sagerx.com.

Allopregnanolone

IUPAC name 1-(3-hydroxy-10,13-dimethyl- 2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro- 1H-cyclopenta[a] phenanthren-17-yl)ethanone
Other names 3α,5α-Tetrahydroprogesterone
Identifiers

PubChem	262961
ChemSpider	17216124
ChEMBL	CHEMBL38856
Jmol-3D images	Image 1

Properties
Molecular formula	C₂₁H₃₄O₂
Molar mass	318.49 g/mol

Allopregnanolone (3α-hydroxy-5α-pregnan-20-one or 3α,5α-tetrahydroprogesterone), generally abbreviated as ALLO or as 3α,5α-THP, is an endogenous inhibitory pregnane neurosteroid.^[1] It is synthesized from progesterone, and is a potent positive allosteric modulator of the GABA_A receptor.^[1] Allopregnanolone has effects similar to those of other potentiators of the GABA_A receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.^[1]

The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions.^[1]

Biosynthesis

The biosynthesis of allopregnanolone starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.^[1]

Depression, anxiety, and sexual dysfunction are frequently-seen side effects of 5α-reductase inhibitors such as finasteride, and are thought to be caused, in part, by interfering with the normal production of allopregnanolone.^[2]

Mechanism

Allopregnanolone acts as a potent positive allosteric modulator of the GABA_A receptor.^[1] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABA_A receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.^[1] Allopregnanolone has also been found to act as a positive allosteric modulator of the GABA_A-ρ receptor, though the implications of this action are unclear.^[3]^[4] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,^[5] and also appears to act as a negative allosteric modulator of the 5-HT₃ receptor.^[6] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptors.^[7]

Unlike progesterone, allopregnanolone is inactive at the nuclear progesterone receptor (nPR).^[7] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which is an agonist of the nPR, and thus/in accordance, allopregnanolone does appear to have indirect nPR-mediated progestogenic effects.^[8] In addition, allopregnanolone has recently been found to be an agonist of the newly-discovered membrane progesterone receptors (mPR), including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABA_A receptor.^[9]^[10] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.^[9]^[11] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.^[7]^[12]

Similarly to many other GABA_A receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),^[13] including α₁ subtypes Ca_v1.2 and Ca_v1.3.^[14] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.^[14] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.^[14] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).^[15] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.^[15]

Function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,^[16] prosocial,^[17] antiaggressive,^[18] prosexual,^[17] sedative, pro-sleep,^[19] cognitive and memory-impairing, analgesic,^[20] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.^[1]

Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.^[21]^[22]^[23]

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression.^[24]^[25]^[26] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABA_A receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.^[24]^[25] This seems to be a common effect of many GABA_A receptor positive allosteric modulators.^[26]^[21] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels), have been found to have negative effects on mood, while higher doses have a neutral effect.^[27]

Therapeutic applications

Allopregnanolone and the other endogenous inhibitory neurosteroids have very short half-lives, and for this reason, have not been pursued for clinical use themselves. Instead, synthetic analogs with improved pharmacokinetic profiles, such as ganaxolone, have been synthesized and are being investigated. However, exogenous progesterone, such as oral micronized progesterone (OMP), reliably elevates allopregnanolone levels in the body with good dose-to-serum level correlations.^[28] Due to this, it has been suggested that OMP could be described as a prodrug of sorts for allopregnanolone.^[28] As a result, there has been some interest in using OMP to treat catamenial epilepsy,^[29] as well as other menstrual cycle-related and neurosteroid-associated conditions.

……………………………………….

http://www.google.com/patents/WO2006037016A2?cl=en

Materials and Methods

[0181] The materials and methods used for the follwing experiments have been described in Griffin L.D., et al, Nature Medicine 10: 704-711 (2004). This reference is hereby incorporated by reference in its entirety.

Example 1: Allopregnanolone Treatment of Niemann Pick type-C Mice Substantially Reduces Accumulation of the Gangliosides GMl, GM2, and GM3 in the Brain [0182] Mice were given a single injection of allopregnanolone, prepared in 20% βcyclodextrin in phosphate buffered saline, at a concentration of 25 mg/kg. The injection was on day 7 of life (P7, postnatal day 7). Concentrations of gangliosides GMl, GM2, GM3, were measured as well as other lipids such as ceramides and cerebrosides.

…………………………………………….

WO-2014031792 OR EQ

http://www.google.com/patents/US20140057885?cl=en

…………………………………….

WO-2013112605

http://www.google.com/patents/WO2013112605A2?cl=en

References

Reddy DS (2010). “Neurosteroids: endogenous role in the human brain and therapeutic potentials”. Prog. Brain Res. 186: 113–37. doi:10.1016/B978-0-444-53630-3.00008-7. PMC 3139029. PMID 21094889.
Römer B, Gass P (December 2010). “Finasteride-induced depression: new insights into possible pathomechanisms”. J Cosmet Dermatol 9 (4): 331–2. doi:10.1111/j.1473-2165.2010.00533.x. PMID 21122055.
Morris KD, Moorefield CN, Amin J (October 1999). “Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids”. Mol. Pharmacol. 56 (4): 752–9. PMID 10496958.
Li W, Jin X, Covey DF, Steinbach JH (October 2007). “Neuroactive steroids and human recombinant rho1 GABAC receptors”. J. Pharmacol. Exp. Ther. 323 (1): 236–47. doi:10.1124/jpet.107.127365. PMID 17636008.
Bullock AE, Clark AL, Grady SR, et al. (June 1997). “Neurosteroids modulate nicotinic receptor function in mouse striatal and thalamic synaptosomes”. J. Neurochem. 68 (6): 2412–23. PMID 9166735.
Wetzel CH, Hermann B, Behl C, et al. (September 1998). “Functional antagonism of gonadal steroids at the 5-hydroxytryptamine type 3 receptor”. Mol. Endocrinol. 12 (9): 1441–51. doi:10.1210/mend.12.9.0163. PMID 9731711.
Mellon SH (October 2007). “Neurosteroid regulation of central nervous system development”. Pharmacol. Ther. 116 (1): 107–24. doi:10.1016/j.pharmthera.2007.04.011. PMC 2386997. PMID 17651807.
Rupprecht R, Reul JM, Trapp T, et al. (September 1993). “Progesterone receptor-mediated effects of neuroactive steroids”. Neuron 11 (3): 523–30. PMID 8398145.
Thomas P, Pang Y (2012). “Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells”. Neuroendocrinology 96 (2): 162–71. doi:10.1159/000339822. PMC 3489003. PMID 22687885.
Pang Y, Dong J, Thomas P (January 2013). “Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors δ and {epsilon} (mPRδ and mPR{epsilon}) and mPRδ involvement in neurosteroid inhibition of apoptosis”. Endocrinology 154 (1): 283–95. doi:10.1210/en.2012-1772. PMC 3529379. PMID 23161870.
Sleiter N, Pang Y, Park C, et al. (August 2009). “Progesterone receptor A (PRA) and PRB-independent effects of progesterone on gonadotropin-releasing hormone release”. Endocrinology 150 (8): 3833–44. doi:10.1210/en.2008-0774. PMC 2717864. PMID 19423765.
Lamba V, Yasuda K, Lamba JK, et al. (September 2004). “PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators”. Toxicol. Appl. Pharmacol. 199 (3): 251–65. doi:10.1016/j.taap.2003.12.027. PMID 15364541.
Hu AQ, Wang ZM, Lan DM, et al. (July 2007). “Inhibition of evoked glutamate release by neurosteroid allopregnanolone via inhibition of L-type calcium channels in rat medial prefrontal cortex”. Neuropsychopharmacology 32 (7): 1477–89. doi:10.1038/sj.npp.1301261. PMID 17151597.
Earl DE, Tietz EI (April 2011). “Inhibition of recombinant L-type voltage-gated calcium channels by positive allosteric modulators of GABAA receptors”. J. Pharmacol. Exp. Ther. 337 (1): 301–11. doi:10.1124/jpet.110.178244. PMC 3063747. PMID 21262851.
Keitel V, Görg B, Bidmon HJ, et al. (November 2010). “The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain”. Glia 58 (15): 1794–805. doi:10.1002/glia.21049. PMID 20665558.
Rougé-Pont F, Mayo W, Marinelli M, Gingras M, Le Moal M, Piazza PV (July 2002). “The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens”. Eur. J. Neurosci. 16 (1): 169–73. PMID 12153544.
Frye CA (December 2009). “Neurosteroids’ effects and mechanisms for social, cognitive, emotional, and physical functions”. Psychoneuroendocrinology. 34 Suppl 1: S143–61. doi:10.1016/j.psyneuen.2009.07.005. PMC 2898141. PMID 19656632.
Pinna G, Costa E, Guidotti A (February 2005). “Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior”. Proc. Natl. Acad. Sci. U.S.A. 102 (6): 2135–40. doi:10.1073/pnas.0409643102. PMC 548579. PMID 15677716.
Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J (October 2012). “Steroid hormones and sleep regulation”. Mini Rev Med Chem 12 (11): 1040–8. PMID 23092405.
Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG (February 2014). “Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain”. Prog. Neurobiol. 113: 70–8. doi:10.1016/j.pneurobio.2013.07.004. PMID 23948490.
Bäckström T, Andersson A, Andreé L, et al. (December 2003). “Pathogenesis in menstrual cycle-linked CNS disorders”. Ann. N. Y. Acad. Sci. 1007: 42–53. PMID 14993039.
Guille C, Spencer S, Cavus I, Epperson CN (July 2008). “The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment”. Epilepsy Behav 13 (1): 12–24. doi:10.1016/j.yebeh.2008.02.004. PMID 18346939.
Finocchi C, Ferrari M (May 2011). “Female reproductive steroids and neuronal excitability”. Neurol. Sci. 32 Suppl 1: S31–5. doi:10.1007/s10072-011-0532-5. PMID 21533709.
Bäckström T, Haage D, Löfgren M, et al. (September 2011). “Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons”. Neuroscience 191: 46–54. doi:10.1016/j.neuroscience.2011.03.061. PMID 21600269.
Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T (September 2009). “Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators”. Psychoneuroendocrinology 34 (8): 1121–32. doi:10.1016/j.psyneuen.2009.02.003. PMID 19272715.
Bäckström T, Bixo M, Johansson M, et al. (February 2014). “Allopregnanolone and mood disorders”. Prog. Neurobiol. 113: 88–94. doi:10.1016/j.pneurobio.2013.07.005. PMID 23978486.
Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T (August 2006). “Allopregnanolone concentration and mood–a bimodal association in postmenopausal women treated with oral progesterone”. Psychopharmacology (Berl.) 187 (2): 209–21. doi:10.1007/s00213-006-0417-0. PMID 16724185.
Andréen L, Spigset O, Andersson A, Nyberg S, Bäckström T (June 2006). “Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone”. Maturitas 54 (3): 238–44. doi:10.1016/j.maturitas.2005.11.005. PMID 16406399.
Orrin Devinsky; Steven Schachter; Steven Pacia (1 January 2005). Complementary and Alternative Therapies for Epilepsy. Demos Medical Publishing. pp. 378–. ISBN 978-1-934559-08-6.

Additional reading

Herd, MB; Belelli, D; Lambert, JJ (2007). Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors. Pharmacol. Ther. 116(1):20-34. doi:10.1016/j.pharmthera.2007.03.007.

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SAGE-547 is a GABA(A) receptor modulator in phase I/II clinical trials at Sage Therapeutics as adjunctive therapy for the treatment of adults with super-refractory status epilepticus (SRSE).

July 22, 2014

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