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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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FDA approves novel treatment Oxbryta (voxelotor) to target abnormality in sickle cell disease

Today, the U.S. Food and Drug Administration granted accelerated approval to Oxbryta (voxelotor) for the treatment of sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older.
“Today’s approval provides additional hope to the 100,000 people in the U.S., and the more than 20 million globally, who live with this debilitating blood disorder,” said Acting FDA Commissioner Adm. Brett P. Giroir, M.D. “Our scientific investments have brought us to a point where we have many more tools available in the battle against sickle cell disease, which presents daily challenges for those living with it. We remain committed to raising the profile of this disease as a public health priority and to approving new therapies that are proven to be safe and effective. Together with improved provider education, patient empowerment, and improved care delivery systems, these newly approved drugs have the potential to immediately impact people living with SCD.”

Sickle cell disease is a lifelong, inherited blood disorder in which red blood cells are abnormally shaped (in a crescent, or “sickle” shape), which restricts the flow in blood vessels and limits oxygen delivery to the body’s tissues, leading to severe pain and organ damage. It is also characterized by severe and chronic inflammation that worsens vaso-occlusive crises during which patients experience episodes of extreme pain and organ damage. Nonclinical studies have demonstrated that Oxbryta inhibits red blood cell sickling, improves red blood cell deformability (ability of a red blood cell to change shape) and improves the blood’s ability to flow.

“Oxbryta is an inhibitor of deoxygenated sickle hemoglobin polymerization, which is the central abnormality in sickle cell disease,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “With Oxbryta, sickle cells are less likely to bind together and form the sickle shape, which can cause low hemoglobin levels due to red blood cell destruction. This therapy provides a new treatment option for patients with this serious and life-threatening condition.”

Oxbryta’s approval was based on the results of a clinical trial with 274 patients with sickle cell disease. In the study, 90 patients received 1500 mg of Oxbryta, 92 patients received 900 mg of Oxbryta and 92 patients received a placebo. Effectiveness was based on an increase in hemoglobin response rate in patients who received 1500 mg of Oxbryta, which was 51.1% for these patients compared to 6.5% in the placebo group.

Common side effects for patients taking Oxbryta were headache, diarrhea, abdominal pain, nausea, fatigue, rash and pyrexia (fever).
Oxbryta was granted Accelerated Approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need based on a result that is reasonably likely to predict a clinical benefit to patients. Further clinical trials are required to verify and describe Oxbryta’s clinical benefit.
The FDA granted this application Fast Track designation. Oxbryta also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Oxbryta to Global Blood Therapeutics.

/////////fda 2019, Fast Track designation,  Oxbryta, Orphan Drug designation, voxelotor, Global Blood Therapeutics, sickle cell disease

FDA approves new treatment XCOPRI (cenobamate tablets) for adults with partial-onset seizures

The U.S. Food and Drug Administration today approved XCOPRI (cenobamate tablets) to treat partial-onset seizures in adults.
“XCOPRI is a new option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Patients can have different responses to the various seizure medicines that are available. This approval provides an additional needed treatment option for people with this condition.”
A seizure is a usually short episode of abnormal electrical activity in the brain. Seizures can cause uncontrolled movements,  abnormal thinking or behavior, and abnormal sensations. Movements can be violent, and changes in consciousness can occur. Seizures occur when clusters of nerve cells (neurons) in the brain undergo uncontrolled activation. A partial-onset seizure begins in a limited area of the brain.
The safety and efficacy of XCOPRI to treat partial-onset seizures was established in two randomized, double-blind, placebo-controlled studies that enrolled 655 adults. In these studies, patients had partial-onset seizures with or without secondary generalization for an average of approximately 24 years and median seizure frequency of 8.5 seizures per 28 days during an 8-week baseline period. During the trials, doses of 100, 200, and 400 milligrams (mg) daily of XCOPRI reduced the percent of seizures per 28 days compared with the placebo group. The recommended maintenance dose of XCOPRI, following a titration (medication adjustment) period, is 200 mg daily; however, some patients may need an additional titration to 400 mg daily, the maximum recommended dose, based on their clinical response and tolerability.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported among patients taking XCOPRI. In the clinical trials, some patients experienced DRESS, and one patient died, when XCOPRI was titrated rapidly (weekly or faster titration). No cases of DRESS were reported in an open-label safety study of 1,339 epilepsy patients when XCOPRI was started at 12.5 mg per day and adjusted every two weeks; however, this finding does not show that the risk of DRESS is prevented by a slower titration. A higher percentage of patients who took XCOPRI also had a shortening of the QT interval (an assessment of certain electrical properties of the heart) of greater than twenty milliseconds compared to placebo. XCOPRI should not be used in patients with hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI or Familial Short QT syndrome. QT shortening can be associated with ventricular fibrillation, a serious heart rhythm problem.
Antiepileptic drugs (AEDs), including XCOPRI, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients taking an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. XCOPRI may cause neurological adverse reactions, including somnolence (sleepiness) and fatigue, dizziness, trouble with walking and coordination, trouble with thinking, and visual changes. Patients should also be advised not to drive or operate machinery until the effect of XCOPRI is known.
The most common side effects that patients in the clinical trials reported were somnolence (sleepiness), dizziness, fatigue, diplopia (double vision), and headaches.
The FDA granted the approval of XCOPRI to SK Life Science Inc.
////////fda 2019, XCOPRI, cenobamate, SK Life Science

FDA approves first treatment Givlaari (givosiran) for inherited rare disease

Today, the U.S. Food and Drug Administration granted approval to Givlaari (givosiran) for the treatment of adult patients with acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules which are formed during the production of heme (which helps bind oxygen in the blood).
“This buildup can cause acute attacks, known as porphyria attacks, which can lead to severe pain and paralysis, respiratory failure, seizures and mental status changes. These attacks occur suddenly and can produce permanent neurological damage and death,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks. The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients.”
The approval of Givlaari was based on the results of a clinical trial of 94 patients with acute hepatic porphyria. Patients received a placebo or Givlaari. Givlaari’s performance was measured by the rate of porphyria attacks that required hospitalizations, urgent health care visits or intravenous infusion of hemin at home. Patients who received Givlaari experienced 70% fewer porphyria attacks compared to patients receiving a placebo.
Common side effects for patients taking Givlaari were nausea and injection site reactions. Health care professionals are advised to monitor patients for anaphylactic (allergic) reaction and renal (kidney) function. Patients should have their liver function tested before and periodically during treatment.
The FDA granted this application Breakthrough Therapy designation and Priority Review designation. Givlaari also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Givlaari to Alnylam Pharmaceuticals.

///////////Givlaari, givosiran, fda 2019, Breakthrough Therapy designation,  Priority ReviewOrphan Drug

Blarcamesine, ブラルカメシン ,






  • Anavex 2-73
  • Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanemethanamine
  • AE-37 / AE37 / ANAVEX 2-73 FREE BASE
  • UNII 9T210MMZ3F
195615-84-0 HCL
Mol weight

Treatment of Rett syndrome, Investigated for use/treatment in breast cancer.

Anti-amnesic, Muscarinic/sigma receptor agonist

  • Originator Anavex Life Sciences
  • Developer ABX-CRO; Anavex Life Sciences; The Michael J. Fox Foundation for Parkinsons Research
  • Class Antidementias; Antidepressants; Antiepileptic drugs; Antiparkinsonians; Anxiolytics; Behavioural disorder therapies; Dimethylamines; Furans; Neuroprotectants; Neuropsychotherapeutics; Nootropics; Small molecules
  • Mechanism of Action Muscarinic receptor modulators; Sigma-1 receptor agonists
  • Orphan Drug Status Yes – Epilepsy; Rett syndrome
  • Phase II/III Alzheimer’s disease
  • Phase II Parkinson’s disease; Rett syndrome
  • Preclinical Amyotrophic lateral sclerosis; Angelman syndrome; Anxiety disorders; Autistic disorder; Fragile X syndrome; Multiple sclerosis
  • No development reported Cognition disorders; Epilepsy; Stroke
  • 28 Oct 2019 No recent reports of development identified for phase-I development in Cognition-disorders in USA
  • 09 Oct 2019 Anavex Life Sciences initiates enrolment in the long term extension ATTENTION-AD trial for Alzheimer’s disease in (country/ies)
  • 02 Oct 2019 Anavex Life Sciences has patent protection covering compositions of matter and methods of treating Alzheimer’s disease for blarcamesine in USA
  • Anavex Life Sciences is developing ANAVEX-2-73 and its active metabolite ANAVEX-19-144, for treating Alzheimer’s disease, epilepsy, stroke and Rett syndrome.

ANAVEX2-73 is an experimental drug is in Phase II trials for Alzheimer’s diseasephase I trials for epilepsy, and in preclinical trials for amyotrophic lateral sclerosisParkinson’s diseaseRett syndrome, stroke.[1][2] ANAVEX2-73 acts as a muscarinic receptor and a moderate sigma1 receptor agonist.[1] ANAVEX2-73 may function as a pro-drug for ANAVEX19-144 as well as a drug itself. ANAVEX19-144 is the active metabolite of ANAVEX 1-41, which is similar to ANAVEX2-73 but it is not as selective for sigma receptor.[2]

Properties and uses

ANAVEX2-73 has an inhibitory constant (ki) lower than 500 nM for all M1–M4 muscarinic acetylcholine receptor subtypes, demonstrating that it acts as a powerful antimuscarinic compound.[2] ANAVEX2-73 was originally tested in mice against the effect of the muscarinic receptor antagonist scopolamine, which induces learning impairment.[1] M1 receptor agonists are known to reverse the amnesia caused by scopolamine.[3] Scopolamine is used in the treatment of Parkinson’s disease and motion sickness by reducing the secretions of the stomach and intestines and can also decreases nerve signals to the stomach.[3] This is via competitive inhibition of muscarinic receptors.[3] Muscarinic receptors are involved in the formation of both short term and long term memories.[1] Experiments in mice have found that M1 and M3 receptor agonists inhibit the formation of amyloid-beta and target GSK-3B.[clarification needed]Furthermore, stimulation of the M1 receptor activates AF267B, which in turn blocks β-secretase, which cleaves the amyloid precursor protein to produce the amyloid-beta peptide. These amyloid-beta peptides aggregate together to form plaques. This enzyme[clarification needed] is involved in the formation of Tau plaques, which are common in Alzheimer’s disease.[clarification needed][4]Therefore. M1 receptor activation appears to decreases tau hyperphosphorylation and amyloid-beta accumulation.[4]

Sigma1 activation appears to be only involved in long-term memory processes. This partly explains why ANAVEX2-73 seems to be more effective in reversing scopolamine-induced long-term memory problems compared to short-term memory deficits.[1] The sigma-1 receptor is located on mitochondria-associated endoplasmic reticulum membranes and modulates the ER stress response and local calcium exchanges with the mitochondria. ANAVEX2-73 prevented Aβ25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2ratio and cytochrome c release into the cytosol, which are indicative of elevated toxicity.[clarification needed] ANAVEX2-73 inhibits mitochondrial respiratory dysfunction and therefore prevents against oxidative stress and apoptosis. This drug prevented the appearance of oxidative stress. ANAVEX2-73 also exhibits anti-apoptotic and anti-oxidant activity. This is due in part because sigma-1 agonists stimulate the anti-apoptoic factor Bcl-2 due to reactive oxygen species dependent transcriptional activation of nuclear factor kB.[5] Results from Marice (2016) demonstrate that sigma1 compounds offer a protective potential, both alone and possibly with other agents like donepezil, an acetylcholinesterase inhibitor, or the memantine, a NMDA receptor antagonist.[6]




Novel crystalline forms of A2-73 (blarcamesine hydrochloride, ANAVEX2-73, AV2-73), a mixed muscarinic receptor ligand and Sig-1 R agonist useful for treating Alzheimer’s disease.




By Foscolos, George B. et alFrom Farmaco, 51(1), 19-26; 1996


  1. Jump up to:a b c d e “Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma” (PDF)Journal of Psychopharmacology. Archived from the original (PDF) on 2015-11-12. Retrieved 2016-05-25.
  2. Jump up to:a b c “ANAVEX 2-73 – AdisInsight” Retrieved 2016-05-25.
  3. Jump up to:a b c Malviya, M; Kumar, YC; Asha, D; Chandra, JN; Subhash, MN; Rangappa, KS (2008). “Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer’s presenile dementia models”. Bioorg Med Chem16: 7095–7101. doi:10.1016/j.bmc.2008.06.053.
  4. Jump up to:a b Leal, NS; Schreiner, B; Pinho, CM; Filadi, R; Wiehager, B; Karlström, H; Pizzo, P; Ankarcrona, M (2016). “Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production”J Cell Mol Med20: 1686–1695. doi:10.1111/jcmm.12863PMC 4988279PMID 27203684.
  5. ^ Lahmy, V; Long, R; Morin, D; Villard, V; Maurice, T (2015-09-28). “Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer’s disease model”Front Cell Neurosci8: 463. doi:10.3389/fncel.2014.00463PMC 4299448PMID 25653589.
  6. ^ Maurice, T (2015-09-28). “Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments”. Behav. Brain Res296: 270–8. doi:10.1016/j.bbr.2015.09.020PMID 26386305.

//////////Blarcamesine, ブラルカメシン , Orphan Drug Status, PHASE 2


LEUPRORELIN, リュープロレリン;



  • Molecular FormulaC59H84N16O12
  • Average mass1209.398 Da
53714-56-0 [RN]
For treatment of prostate cancer, endometriosis, uterine fibroids and premature puberty
Leuprolide acetate 37JNS02E7V 74381-53-6

Synthesis Reference, Daniel Kadzimirzs, Gerhard Jas, Volker Autze, “Solution-Phase Synthesis of Leuprolide and Its Intermediates.” U.S. Patent US20090005535, issued January 01, 2009.US20090005535

CAS Registry Number: 53714-56-0
CAS Name: 6-D-Leucine-9-(N-ethyl-L-prolinamide)-10-deglycinamideluteinizing hormone-releasing factor (pig)
Additional Names: leuprorelin; (D-Leu6)-des-Gly10-LH-RH-ethylamide
Molecular Formula: C59H84N16O12
Molecular Weight: 1209.40
Percent Composition: C 58.59%, H 7.00%, N 18.53%, O 15.88%
Literature References: Synthetic nonapeptide agonist analog of LH-RH, q.v. Prepn: M. Fujino et al., DE 2446005 (1975 to Takeda), C.A. 83, 10895y (1975); R. L. Gendrich et al., US 4005063 (1977 to Abbott). Synthesis: J. A. Vilchez-Martinez et al.,Biochem. Biophys. Res. Commun. 59, 1226 (1974); M. Fujino et al., ibid. 60, 406 (1974). Comparison of biological activity with natural LH-RH: D. H. Coy et al., ibid. 67, 576 (1975). Pharmacokinetics: L. T. Sennello et al., J. Pharm. Sci. 75, 158 (1986). Clinical efficacy in prostatic carcinoma: M. B. Garnick et al., N. Engl. J. Med. 311, 1281 (1984); in benign prostatic hypertrophy: L. M. Eri, K. J. Tveter, J. Urol. 150, 359 (1993). Clinical trial in endometriosis: J. M. Wheeler et al., Am. J. Obstet. Gynecol. 167, 1367 (1992).
Properties: Fluffy solid. [a]D25 -31.7° (c = 1 in 1% acetic acid).
Optical Rotation: [a]D25 -31.7° (c = 1 in 1% acetic acid)
Derivative Type: Monoacetate (salt)
CAS Registry Number: 74381-53-6
Additional Names: Leuprolide acetate
Manufacturers’ Codes: Abbott 43818; A-43818; TAP-144
Trademarks: Carcinil (Abbott); Eligard (Sanofi-Aventis); Enantone (Takeda); Leuplin (Takeda); Lucrin (Abbott); Lupron (TAP); Prostap (Wyeth); Viadur (Alza)
Molecular Formula: C59H84N16O12.C2H4O2
Molecular Weight: 1269.45
Percent Composition: C 57.71%, H 6.99%, N 17.65%, O 17.64%
Therap-Cat: Antineoplastic (hormonal); LH-RH agonist.
Keywords: Antineoplastic (Hormonal); LH-RH Analogs; LH-RH Agonist.
Leuprolide belongs to the general class of drugs known as hormones or hormone antagonists. It is a synthetic 9 residue peptide analog of gonadotropin releasing hormone. Leuprolide is used to treat advanced prostate cancer. It is also used to treat uterine fibroids and endometriosis. Leuprolide is also under investigation for possible use in the treatment of mild to moderate Alzheimer’s disease.

Jitsubo , a subsidiary of  Sosei , was investigating JIT-1007 , presumed to be a biosimilar version of an undisclosed peptide therapeutic, generated using its proprietary Molecular Hiving, for the treatment of an unidentified indication, however no development has been reported for some time, this program is assumed to be discontinued.

Leuprorelin, also known as leuprolide, is a manufactured version of a hormone used to treat prostate cancerbreast cancerendometriosisuterine fibroids, and early puberty.[1][2] It is given by injection into a muscle or under the skin.[1]

Common side effects include hot flashes, unstable mood, trouble sleepingheadaches, and pain at the site of injection.[1] Other side effects may include high blood sugarallergic reactions, and problems with the pituitary gland.[1] Use during pregnancy may harm the baby.[1] Leuprorelin is in the gonadotropin-releasing hormone (GnRH) analogue family of medications.[1] It works by decreasing gonadotropin and therefore decreasing testosterone and estradiol.[1]

Leuprorelin was patented in 1973 and approved for medical use in the United States in 1985.[1][3] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[4] In the United Kingdom a monthly dose costs the NHS about GB£75.24.[5] In the United States the equivalent dose has a wholesale cost of US$1,011.93.[6] It is sold under the brand name Lupron among others.[1]

Medical use

Leuprorelin may be used in the treatment of hormone-responsive cancers such as prostate cancer and breast cancer. It may also be used for estrogen-dependent conditions such as endometriosis[7] or uterine fibroids.

It may be used for precocious puberty in both males and females,[8] and to prevent premature ovulation in cycles of controlled ovarian stimulation for in vitro fertilization (IVF).

It may be used to reduce the risk of premature ovarian failure in women receiving cyclophosphamide for chemotherapy.[9]

Along with triptorelin and goserelin, it is has been used to delay puberty in transgender youth until they are old enough to begin hormone replacement therapy.[10] Researchers have recommended puberty blockers after age 12, when the person has developed to Tanner stages 2-3, and then cross-sex hormones treatment at age 16. This use of the drug is off-label, however, not having been approved by the Food and Drug Administration and without data on long-term effects of this use.[11]

They are also sometimes used as alternatives to antiandrogens like spironolactone and cyproterone acetate for suppressing testosterone production in transgender women.[citation needed]

It is considered a possible treatment for paraphilias.[12] Leuprorelin has been tested as a treatment for reducing sexual urges in pedophiles and other cases of paraphilia.[13][14]

Side effects

Common side effects of Lupron Injection include redness/burning/stinging/pain/bruising at the injection site, hot flashes (flushing), increased sweating, night sweats, tiredness, headache, upset stomach, nausea, diarrhea, constipation, stomach pain, breast swelling or tenderness, acne, joint/muscle aches or pain, trouble sleeping (insomnia), reduced sexual interest, vaginal discomfort/dryness/itching/discharge, vaginal bleeding, swelling of the ankles/feet, increased urination at night, dizziness, breakthrough bleeding in a female child during the first 2 months of leuprorelin treatment, weakness, chills, clammy skin, skin redness, itching, or scaling, testicle pain, impotence, depression, or memory problems.[15] The rates of gynecomastia with leuprorelin have been found to range from 3 to 16%.[16]

Mechanism of action

Leuprorelin is a gonadotropin-releasing hormone (GnRH) analogue acting as an agonist at pituitary GnRH receptors. Agonism of GnRH receptors initially results in the stimulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion by the anterior pituitary ultimately leading to increased serum estradiol and testosterone levels via the normal physiology of the hypothalamic–pituitary–gonadal axis (HPG axis); however, because propagation of the HPG axis is incumbent upon pulsatile hypothalamic GnRH secretion, pituitary GnRH receptors become desensitised after several weeks of continuous leuprorelin therapy. This protracted downregulation of GnRH receptor activity is the targeted objective of leuprorelin therapy and ultimately results in decreased LH and FSH secretion, leading to hypogonadism and thus a dramatic reduction in estradiol and testosterone levels regardless of sex.[17][18]

In the treatment of prostate cancer, the initial increase in testosterone levels associated with the initiation of leuprorelin therapy is counterproductive to treatment goals. This effect is avoided with concurrent utilisation of 5α-reductase inhibitors, such as finasteride, which function to block the downstream effects of testosterone.


The peptide sequence is Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt (Pyr = LPyroglutamyl).


Leuprorelin was discovered and first patented in 1973 and was introduced for medical use in 1985.[19][20] It was initially marketed only for daily injection, but a depot injectionformulation was introduced in 1989.[20]

Society and culture


Leuprorelin is the generic name of the drug and its INN and BAN, while leuprorelin acetate is its BANM and JANleuprolide acetate is its USAN and USPleuprorelina is its DCIT, and leuproréline is its DCF.[21][22][23][24] It is also known by its developmental code names A-43818Abbott-43818DC-2-269, and TAP-144.[21][22][23][24]

Leuprorelin is marketed by Bayer AG under the brand name Viadur, by Tolmar under the brand name Eligard, and by TAP Pharmaceuticals (1985–2008), by Varian Darou Pajooh under the brand name Leupromer and Abbott Laboratories (2008–present) under the brand name Lupron. It is available as a slow-release implant or subcutaneous/intramuscular injection.

In the UK and Ireland, leuprorelin is marketed by Takeda UK as Prostap SR (one-month injection) and Prostap 3 (three-month injection).


Available formsLupron injection was first approved by the FDA for treatment of advanced prostate cancer on April 9, 1985.

  • Lupron depot for monthly intramuscular injection was first approved by the FDA for palliative treatment of advanced prostate cancer on January 26, 1989, and subsequently in 22.5 mg/vial and 30 mg/vial for intramuscular depot injection every 3 and 4 months, respectively. 3.75 mg/vial and 11.25 mg/vial dosage forms were subsequently approved for subcutaneous depot injection every month and every 3 months, respectively for treatment of endometriosis or fibroids. 7.5 mg/vial, 11.25 mg/vial, and 15 mg/vial dosage forms were subsequently approved for subcutaneous depot injection for treatment of children with central precocious puberty.
  • Viadur (72 mg yearly subcutaneous implant) was first approved by the FDA for palliative treatment of advanced prostate cancer on March 6, 2000. Bayer will fulfill orders until current supplies are depleted, expected by the end of April 2008
  • Eligard (7.5 mg for monthly subcutaneous depot injection) was first approved by the FDA for palliative treatment of advanced prostate cancer on January 24, 2002, and subsequently in 22.5 mg, 30 mg, and 45 mg doses for subcutaneous depot injection every 3, 4, and 6 months, respectively.
  • Leupromer 7.5 (7.5 mg, one month depot for subcutaneous injection) is the second in situ-forming injectable drug in the world. It is used for palliative treatment of advanced prostate cancer, endometriosis, and uterine fibroids. It was approved by The Ministry of Health and Medical Education Of Iran.

Leuprorelin is available in the following forms, among others:[25][26][27]

  • Short-acting daily intramuscular injection (Lupron): 5 mg/mL (2.8 mL) used as 1 mg every day.
  • Long-acting depot intramuscular injection (Lupron Depot): 7.5 mg once a month, 22.5 mg every 3 months, or 30 mg every 4 months.
  • Long-acting depot subcutaneous injection (Eligard): 7.5 mg once a month, 22.5 mg every 3 months, 30 mg every 4 months, or 45 mg every 6 months.
  • Long-acting subcutaneous implant (Viadur): 65 mg pellet once every 12 months.

“Lupron protocol”

A 2005 paper in the controversial and non-peer reviewed journal Medical Hypotheses suggested leuprorelin as a possible treatment for autism,[28] the hypothetical method of action being the now defunct hypothesis that autism is caused by mercury, with the additional unfounded assumption that mercury binds irreversibly to testosterone and therefore leuprorelin can help cure autism by lowering the testosterone levels and thereby mercury levels.[29] However, there is no scientifically valid or reliable research to show its effectiveness in treating autism.[30] This use has been termed the “Lupron protocol”[31] and Mark Geier, the proponent of the hypothesis, has frequently been barred from testifying in vaccine-autism related cases on the grounds of not being sufficiently expert in that particular issue[32][33][34] and has had his medical license revoked.[31] Medical experts have referred to Geier’s claims as “junk science”.[35]

Veterinary use

Leuprorelin is frequently used in ferrets for the treatment of adrenal disease. Its use has been reported in a ferret with concurrent primary hyperaldosteronism,[36] and one with concurrent diabetes mellitus.[37]


As of 2006 leuprorelin was under investigation for possible use in the treatment of mild to moderate Alzheimer’s disease.[38]

by mouth formulation of leuprorelin is under development for the treatment of endometriosis.[39] It was also under development for the treatment of precocious pubertyprostate cancer, and uterine fibroids, but development for these uses was discontinued.[39] The formulation has the tentative brand name Ovarest.[39] As of July 2018, it is in phase II clinical trials for endometriosis.[39]



Process for producing leuprorelin as LH-RH (GnRH) agonist useful for treating endometriosis, uterine fibroids, premenopausal breast cancer and prostate cancer.





  1. Jump up to:a b c d e f g h i “Leuprolide Acetate”. The American Society of Health-System Pharmacists. Archived from the original on 23 December 2016. Retrieved 8 December2016.
  2. ^ “19th WHO Model List of Essential Medicines (April 2015)” (PDF). WHO. April 2015. Archived (PDF) from the original on May 13, 2015. Retrieved May 10, 2015.
  3. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 514. ISBN 9783527607495.
  4. ^ “WHO Model List of Essential Medicines (19th List)” (PDF)World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  5. ^ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 655. ISBN 9780857111562.
  6. ^ “NADAC as of 2016-12-07 |”Centers for Medicare and Medicaid ServicesArchived from the original on 21 December 2016. Retrieved 23 December 2016.
  7. ^ Crosignani PG, Luciano A, Ray A, Bergqvist A (January 2006). “Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain”. Human Reproduction21 (1): 248–56. doi:10.1093/humrep/dei290PMID 16176939.
  8. ^ Badaru A, Wilson DM, Bachrach LK, et al. (May 2006). “Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty”. The Journal of Clinical Endocrinology and Metabolism91 (5): 1862–7. doi:10.1210/jc.2005-1500PMID 16449344.
  9. ^ Clowse ME, Behera MA, Anders CK, Copland S, Coffman CJ, Leppert PC, Bastian LA (March 2009). “Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis”Journal of Women’s Health18 (3): 311–9. doi:10.1089/jwh.2008.0857PMC 2858300PMID 19281314.
  10. ^ David A. Wolfe; Eric J. Mash (9 October 2008). Behavioral and Emotional Disorders in Adolescents: Nature, Assessment, and Treatment. Guilford Press. pp. 556–. ISBN 978-1-60623-115-9Archived from the original on 2 July 2014. Retrieved 24 March 2012.
  11. ^ Dreger, A. (2009, Jan.-Feb.). Gender Identity Disorder in childhood: Inconclusive advice to parents. Hastings Center Report, pp. 26-29.
  12. ^ Saleh FM, Niel T, Fishman MJ (2004). “Treatment of paraphilia in young adults with leuprolide acetate: a preliminary case report series”. Journal of Forensic Sciences49 (6): 1343–8. doi:10.1520/JFS2003035PMID 15568711.
  13. ^ Schober JM, Byrne PM, Kuhn PJ (2006). “Leuprolide acetate is a familiar drug that may modify sex-offender behaviour: the urologist’s role”. BJU International97 (4): 684–6. doi:10.1111/j.1464-410X.2006.05975.xPMID 16536753.
  14. ^ Schober JM, Kuhn PJ, Kovacs PG, Earle JH, Byrne PM, Fries RA (2005). “Leuprolide acetate suppresses pedophilic urges and arousability”. Archives of Sexual Behavior34 (6): 691–705. doi:10.1007/s10508-005-7929-2PMID 16362253.
  15. ^ “Common Side Effects of Lupron (Leuprolide Acetate Injection) Drug Center”Archived from the original on 2015-07-29. Retrieved 2015-07-26.[full citation needed]
  16. ^ Di Lorenzo G, Autorino R, Perdonà S, De Placido S (December 2005). “Management of gynaecomastia in patients with prostate cancer: a systematic review”. Lancet Oncol6 (12): 972–9. doi:10.1016/S1470-2045(05)70464-2PMID 16321765.
  17. ^ Mutschler E, Schäfer-Korting M (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 372–3. ISBN 978-3-8047-1763-3.
  18. ^ Wuttke W, Jarry H, Feleder C, Moguilevsky J, Leonhardt S, Seong JY, Kim K (1996). “The neurochemistry of the GnRH pulse generator”Acta Neurobiologiae Experimentalis56(3): 707–13. PMID 8917899Archived from the original on 2015-12-08.
  19. ^ Jamil, George Leal (30 September 2013). Rethinking the Conceptual Base for New Practical Applications in Information Value and Quality. IGI Global. pp. 111–. ISBN 978-1-4666-4563-9.
  20. Jump up to:a b Hara T (1 January 2003). Innovation in the Pharmaceutical Industry: The Process of Drug Discovery and Development. Edward Elgar Publishing. pp. 106–107. ISBN 978-1-84376-566-0.
  21. Jump up to:a b J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 730–. ISBN 978-1-4757-2085-3.
  22. Jump up to:a b Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 599–. ISBN 978-3-88763-075-1.
  23. Jump up to:a b I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 164–. ISBN 978-94-011-4439-1.
  24. Jump up to:a b “Leuprorelin”.
  25. ^ Sara K. Butler; Ramaswamy Govindan (25 October 2010). Essential Cancer Pharmacology: The Prescriber’s Guide. Lippincott Williams & Wilkins. pp. 262–. ISBN 978-1-60913-704-5.
  26. ^ Richard A. Lehne; Laura Rosenthal (25 June 2014). Pharmacology for Nursing Care – E-Book. Elsevier Health Sciences. pp. 1296–. ISBN 978-0-323-29354-9.
  27. ^ Prostate Cancer. Demos Medical Publishing. 20 December 2011. pp. 503–. ISBN 978-1-935281-91-7.
  28. ^ Geier M, Geier D (2005). “The potential importance of steroids in the treatment of autistic spectrum disorders and other disorders involving mercury toxicity”. Med Hypotheses64 (5): 946–54. doi:10.1016/j.mehy.2004.11.018PMID 15780490.
  29. ^ Allen A (2007-05-28). “Thiomersal on trial: the theory that vaccines cause autism goes to court”SlateArchived from the original on 2008-02-03. Retrieved 2008-01-30.
  30. ^ “Testosterone regulation”. Research Autism. 2007-05-07. Archived from the original on 2015-04-18. Retrieved 2015-04-09.
  31. Jump up to:a b “Maryland medical board upholds autism doctor’s suspension”Chicago Tribune. May 11, 2011. Archived from the original on October 21, 2011.
  32. ^ John and Jane Doe v. Ortho-Clinical Diagnostics, Inc Archived 2008-03-06 at the Wayback Machine“, US District Court for the Middle District of North Carolina, July 6, 2006
  33. ^ Dr. Mark Geier Severely Criticized Archived 2016-12-02 at the Wayback Machine“, Stephen Barrett, M.D.,
  34. ^ Mills S, Jones T (2009-05-21). “Physician team’s crusade shows cracks”Chicago TribuneArchived from the original on 2009-05-25. Retrieved 2009-05-21.
  35. ^ ‘Miracle drug’ called junk science: Powerful castration drug pushed for autistic children, but medical experts denounce unproven claims Archived 2013-12-03 at the Wayback MachineChicago Tribune, May 21, 2009
  36. ^ Desmarchelier M, Lair S, Dunn M, Langlois I (2008). “Primary hyperaldosteronism in a domestic ferret with an adrenocortical adenoma”. Journal of the American Veterinary Medical Association233 (8): 1297–301. doi:10.2460/javma.233.8.1297PMID 19180717.
  37. ^ Boari A, Papa V, Di Silverio F, Aste G, Olivero D, Rocconi F (2010). “Type 1 diabetes mellitus and hyperadrenocorticism in a ferret”. Veterinary Research Communications34(Suppl 1): S107–10. doi:10.1007/s11259-010-9369-2PMID 20446034.
  38. ^ Doraiswamy PM, Xiong GL (2006). “Pharmacological strategies for the prevention of Alzheimer’s disease”. Expert Opinion on Pharmacotherapy7 (1): 1–10. doi:10.1517/14656566.7.1.S1PMID 16370917.
  39. Jump up to:a b c d “Leuprorelin oral – Enteris BioPharma – AdisInsight” Retrieved 16 July 2018.

External links

Leuprorelin ball-and-stick.png
Clinical data
Trade names Lupron, Eligard, Lucrin, others
Synonyms Leuprolide; Leuprolidine; A-43818; Abbott-43818; DC-2-269; TAP-144
AHFS/ Consumer Drug Information
MedlinePlus a685040
  • X
Routes of
Drug class GnRH analogueGnRH agonistAntigonadotropin
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life 3 hours
Excretion Kidney
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.161.466 Edit this at Wikidata
Chemical and physical data
Formula C59H84N16O12
Molar mass 1209.421 g·mol−1
3D model (JSmol)

//////////LEUPRORELIN, リュープロレリン ,




  • Molecular FormulaC28H27ClF5NO
  • Average mass523.965 Da
CAS Registry Number: 26864-56-2
CAS Name: 1-[4,4-Bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol
Additional Names: 1-[4,4-bis(p-fluorophenyl)butyl]-4-(4-chloro-a,a,a-trifluoro-m-tolyl)-4-piperidinol; 1-(4,4-bis(4-fluorophenyl)butyl)-4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine
Manufacturers’ Codes: R-16341
MCN-JR-16,341 / R 16,341
Trademarks: Semap (Janssen)
Molecular Formula: C28H27ClF5NO
Molecular Weight: 523.97
Percent Composition: C 64.18%, H 5.19%, Cl 6.77%, F 18.13%, N 2.67%, O 3.05%
Literature References: Prepn: H. K. F. Hermans, C. J. E. Niemegeers, DE 2040231eidem, US 3575990 (both 1971 to Janssen); Sindelár et al., Collect. Czech. Chem. Commun. 38, 3879 (1973). Pharmacology and toxicology: Janssen et al., Eur. J. Pharmacol.11, 139 (1970). Crystal structure: Koch, Acta Crystallogr. 29B, 1538 (1973).
Properties: White, microcrystals, mp 105-107°. Slightly sol in water, dil HCl (<0.5 mg/ml). LD50 orally in mice (day 7): 86.8 mg/kg (Janssen).
Melting point: mp 105-107°
Toxicity data: LD50 orally in mice (day 7): 86.8 mg/kg (Janssen)
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic.
Penfluridol (SemapMicefalLongoperidol) is a highly potent, first generation diphenylbutylpiperidine antipsychotic.[1] It was discovered at Janssen Pharmaceutica in 1968.[2] Related to other diphenylbutylpiperidine antipsychotics, pimozide and fluspirilene, penfluridol has an extremely long elimination half-life and its effects last for many days after single oral dose. Its antipsychotic potency, in terms of dose needed to produce comparable effects, is similar to both haloperidol and pimozide. It is only slightly sedative, but often causes extrapyramidal side-effects, such as akathisiadyskinesiae and pseudo-Parkinsonism. Penfluridol is indicated for antipsychotic treatment of chronic schizophrenia and similar psychotic disorders, it is, however, like most typical antipsychotics, being increasingly replaced by the atypical antipsychotics. Due to its extremely long-lasting effects, it is often prescribed to be taken orally as tablets only once a week (q 7 days). The once-weekly dose is usually 10–60 mg. A 2006 systematic review examined the use of penfluridol for people with schizophrenia:
Penfluridol compared to typical antipsychotics (oral) for schizophrenia[3]
Although there are shortcomings and gaps in the data, there appears to be enough overall consistency for different outcomes. The effectiveness and adverse effects profile of penfluridol are similar to other typical antipsychotics; both oral and depot. Furthermore, penfluridol is shown to be an adequate treatment option for people with schizophrenia, especially those who do not respond to oral medication on a daily basis and do not adapt well to depot drugs. One of the results favouring penfluridol was a lower drop out rate in medium term when compared to depot medications. It is also an option for people with long-term schizophrenia with residual psychotic symptoms who nevertheless need continuous use of antipsychotic medication. An additional benefit of penfluridol is that it is a low-cost intervention.[3]


    • ATC:N05AG03
  • Use:neuroleptic
  • Chemical name:1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol
  • Formula:C28H27ClF5NO
  • MW:523.97 g/mol
  • CAS-RN:26864-56-2
  • EINECS:248-074-5
  • LD50:87 mg/kg (M, p.o.);
    160 mg/kg (R, p.o.)



Late stage functionalization of secondary amines via a cobalt-catalyzed electrophilic amination of organozinc reagents
Org Lett 2019, 21(2): 494

Scheme 6

Scheme 6. A New Synthesis of Penfluridol 5
str1 str2

English: DE patent 2040231

US patent 3575990


File:Penfluridol synthesis.png



    • US 3 575 990 (Janssen; 20.4.1971; appl. 3.9.1969).
    • DOS 2 040 231 (Janssen; appl. 13.8.1970; USA-prior. 3.9.1969).
  • alternative synthesis:

    • FR-appl. 2 161 007 (Janssen; appl. 23.11.1972; J-prior. 25.11.1971).


Although Penfluridol listed for many years, but its chemical preparation technology abroad little studied in the earlier literature, there are several prepared as follows:

[0013] Process (a): 1971 Document Ger.0ffen [P], 2040231, (1971) Hermans.HKF first reported Penfluridol chemical synthesis, which process is as follows:


Figure CN106187863AD00101

[0015] The process of cyclopropyl methanol (ΙΠ) by 4,4, _-difluorophenyl-one ([pi) as a starting material, the reaction of cyclopropyl magnesium bromide-bis 4- (fluorophenyl), then the reaction with thionyl chloride to give 1,1_-bis (4-fluorophenyl) -4-chloro-butene (IV), obtained by catalytic hydrogenation 1,1_-bis (4-phenyl gas) burning chlorobutanol _4_ (V), and finally with 4-chloro-3-methylphenyl gas-4-piperidinol (X VH) in methyl isobutyl ketone was refluxed for three days the reaction to produce Penfluridol (the I), Document: al, Collect Czech.Chem.Commun [J], 38 (12): 3879-3901, (1973).

[0016] In the above process, starting material and documentation of cyclopropyl magnesium bromide hardly prepared each reaction were not reported preparation yield, and therefore Document Sindelar · K · et al, Collect Czech · Chem · Commun [ J], 38 (12):. 3879-3901, (1973) that this technology is not very good.

[0017] Process (b): 1973, Sindelar.K successful research and the following other technology, which process is as follows:


Figure CN106187863AD00111

[0019] The process consists of 4,4_-bis (4-fluorophenyl) butoxy alkyl iodide as a starting material, 4,4_ ethylenedioxythiophene condensing piperidone removal of generated hydrogen iodide in N-pentanone – [4,4-bis (4-fluorophenyl) butoxy group] -4,4-dioxo-condensing vinyl piperidone, N-then obtained by acid hydrolysis [4,4-bis (4-fluorophenyl ) azetidinyl] -4-piperidone (W), the compound (W) with 4-chloro-3-trifluoromethyl phenyl magnesium bromide reacted Penfluridol (I).

[0020] This process route may seem simple, but there are more desired to prepare intermediates, the process is more complex, with low yields reported in the literature.

[0021] Process (c): as follows:


Figure CN106187863AD00121

[0023] In this process, 4-chloro – (4-fluorophenyl) butyryl-one (Shan) starts, 4-fluorophenyl magnesium bromide reacts with 4-chloro – bis (4-fluorophenyl) butanol ( IX), and then boiling the reaction hydroiodic acid to give 4-iodo-in, red phosphorus catalyst – bis (4-fluorophenyl) butoxy left foot and finally burning ^^ – ^ – methyl ^ two gas – chlorophenyl Bu ‘piperidinol prepared products San ^ top five gas profitable ⑴.

[0024] This synthesis has the characteristics of high yield, but the intermediate (IX), (X) quality is not purified, many by-products, difficult to control the quality of products, and hydroiodic acid to be used, the source of raw material is difficult, therefore, not ideal technology.

[0025] Process (d), as follows:


Figure CN106187863AD00131

[0027] The process begins by Stobber reaction with 4,4 – fluorophenyl ketone reaction product diethyl succinate and compound (XI), and then generates bis (4-fluorophenyl) methine acid or base hydrolysis after succinic acid (M), by catalytic hydrogenation to give 4,4_-bis (4-fluorophenyl) butanoic acid after, the reaction with thionyl chloride without isolating the compound (XIV) with the compound directly (XW), by reduction after obtain the final product – Penfluridol. The disadvantage of this process is that, in the above reaction step, Stobber the reaction yield is low; hydrogenation catalyst manufacturing operation more difficult and unsafe; reaction with thionyl chloride, large air pollution, and other refractory.

[0028] The various preparation techniques Penfluridol other drug earlier British Patent Brit. 1141664 and German patent Ger. Off en. 2040231 has been reported, but no other foreign patent reports. In neither country has patent coverage, and no magazine reported.

 The reaction formula is as follows:


Figure CN106187863AD00151

[0059] Step (5), the preparation of compounds of formula (XW) as shown, may be employed a method reported in the literature, or prepared using a method specifically includes the following steps:


Figure CN106187863AD00161

0124] (6) Penfluridol drug (I) were prepared:


Figure CN106187863AD00221

[0126] In three 500ml reaction flask equipped with a mechanical stirrer, a condenser, a thermometer, a calcium chloride tube, was added 250ml of anhydrous diethyl ether, 2 · 4g (0 · 0631mol) tetrahydro lithium aluminum hydride, stirring was started, was added 20g (0 · 0372mol) amide (6), the addition was completed, 38 ° C for 6 hours.

[0127] completion of the reaction, water was added 4.2ml decomposition for 25 minutes, followed by addition of 5.4ml of 20% by weight concentration of sodium hydroxide solution decomposition for 20 minutes, 14.2ml decomposed with water for 15 minutes;

[0128] The decomposition was filtered, the filtrate (ethyl ether) and dried over anhydrous potassium carbonate. Filtered, the filter cake was washed with a little ether. The filtrate and the washings added to a distillation flask, recovery ether atmospheric distillation, vacuum drained, was added a mixed solvent l〇〇ml [chloroform: petroleum ether (60-90 ° C) = 1: 4, weight ratio, stirred and heated to reflux dissolution, filtered while hot, the filtrate was allowed to stand for crystallization at about 10 ° C, to be naturally deposited crystal after freezing -5 ° C overnight, filtered, the cake was washed with a mixed solvent, drain, ventilation pressure at 70 ° C dried to constant weight to give white crystalline product Penfluridol drug (I), mp 105-107 ° C, yield 81.5%.

[0129] Intermediate 4_ (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (XW) (referred piperidinol) Preparation:

[0130] (1) benzylamine (Beta) Preparation:


Figure CN106187863AD00222

[0132] equipped with a mechanical stirrer, a condenser, a thermometer 2000ml three reaction bottle, were added ammonium bicarbonate 240g (3.04mol), aqueous ammonia at a concentration of 20 wt %% of 15148 (17.812111〇1,

[0133] 1640ml), benzyl chloride 80g (0.632mol), reaction was stirred for 6 hours.Reaction to complete rested stratification. Aqueous layer was separated, and aqueous ammonia recovery bicarbonate atmospheric heating to 100 ° c, the water was distilled off under reduced pressure, with 50% sodium hydroxide PH12 above, extraction with benzene and dried solid sodium hydroxide. Recovery of benzene atmospheric distillation, vacuum distillation, collecting 33.4 g of the product obtained, yield 50.7%, content 99%,


Figure CN106187863AD00223

[0135] (3) N_ benzyl – bis ([beta] methoxycarbonyl-ethyl) amine (C) (referred to as diester thereof):


Figure CN106187863AD00231

[0137] The reaction flask equipped with a mechanical stirrer, a condenser, a thermometer three 250ml, 43g methyl acrylate (0.5111〇1) methanol 328 (401111), was added with stirring 21.48 benzylamine (0.2111〇1), The reaction was stirred for 7 hours. Completion of the reaction, recovery of excess methyl acrylate and methanol, water chestnut vacuum distillation until the internal temperature l〇〇-ll〇 ° C, to give the crude product as a yellow oil (C) 54g, yield 97%, content 94.3%.

[0138] (3) 1 – benzyl-4-piperidone (E) (referred to as the hydrolyzate) is prepared:


Figure CN106187863AD00232

[0140] In a reaction flask equipped with a 500ml three mechanical stirrer, thermometer, fractional distillation apparatus, was added 27% sodium methoxide 27g, crude diester was 33.4g (0.12mol), toluene 300ml, stirred and heated, the temperature reached 90 when ° C or more, additional 50ml toluene was reacted for 3 hours. Cooled to room temperature, and neutralized with acetic acid to PH6, standing layer. The toluene layer was separated and extracted with 150ml of 22% hydrochloric acid three times. Hydrochloric acid extracts were combined, heated with stirring for 4 hours. Recovered by distillation under reduced pressure and hydrochloric acid (about 120ml distilled dilute hydrochloric acid) was cooled to distillation l〇 ° C below, with 40% sodium hydroxide PH12 above. With 80ml ethyl acetate 3 times extracted with ethyl acetate extracts were combined, sub-net water, dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, recovering ethyl acetate atmospheric distillation, vacuum drained hydrolyzed to give (E) and the crude product 19g, yield 84%.

Figure CN106187863AD00233

[0141] (4) 1-ethoxycarbonyl-4-piperidone (F) (referred to as a carbonyl group-piperidone) Preparation:


Figure CN106187863AD00234

[0143] equipped with a mechanical stirrer, a condenser, 250ml three reaction flask thermometer, was added ethyl chloroformate 23.9g (0 · 22mo 1), benzene 100ml, stirring slowly added dropwise [The crude hydrolyzate (E ) 37 · 8g (0 · 2mo 1) + 20ml phenyl] solution dropwise, the reaction was heated with stirring for 5 hours.Water chestnut evaporated under reduced pressure and ethyl benzene chlorine, Li mechanical change stream distilled off under reduced pressure, low boiling point evaporated to give the product 268 was collected, yield 76%.

[0144] (5) 1 – ethoxycarbonyl-4- (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (G) (referred to as a carbonyl group-piperidinol) is:


Figure CN106187863AD00241

[0146] In three 500ml reaction flask equipped with a mechanical stirrer, a condenser, a thermometer, a dropping funnel and a calcium chloride drying tube over anhydrous anhydrous absolute, at room temperature was added magnesium metal shoulder 2.5g (0.103mol) 20ml of anhydrous ethyl ether and slowly stirring was started.

[0147] 2-chloro-5-bromo – trifluorotoluene (referred bromide) was dissolved under 27g (0.104mol) at room temperature in 130ml anhydrous diethyl ether and stirred to obtain a uniform liquid mass (W is);

[0148] When the liquid material taken (W) 15ml was added to the above reaction, a solution of iodine 0.13g, 1,2- dibromoethane 0.2g, initiated Grignard reaction was heated until the iodine color disappeared, the reaction slowed down, slow slow dropping liquid material (W). The addition was completed, refluxing was continued for 1 hour. Completion of the reaction, cooled to room temperature, slowly added dropwise at room temperature carbonyl piperidone (F) water solution was cooled at normal [carbonyl-piperidone 13.6g (0.0795mol) + 40ml dry ether], dropwise, the reaction was heated with stirring 1.5 hour. L〇〇ml ammonium chloride solution concentration of 20% by weight was added, refluxed for 15 minutes and allowed to stand 30 minutes at room temperature stratification. Discharged aqueous layer (lower layer), the residual liquid was distilled (upper layer) at an external temperature of 55 ° C atmospheric distillation recovery ether, discharge hot, refrigerated overnight, the precipitated solid. Filtered, washed with a small amount of time, drained, and dried to give the product (G) 24.1g, yield 85.7%, mp 118-126Γ.

[0149] (6) 4- (3-trifluoromethyl-4-chlorophenyl) -4-piperidinol (X VH) (referred piperidinol) Preparation:


Figure CN106187863AD00242

[0151] equipped with a mechanical stirrer, a condenser, 250ml three reaction flask thermometer, were added ethanol 40ml, 158 of sodium hydroxide (0.375111〇1), carbonyl piperidinol (6) 2 (^ (0.0569111〇1 ), heated to reflux, and the reaction stirred for 3.5 hours. the reaction was completed, 50ml of water was added, the reaction was refluxed for 10 minutes, the hot reaction solution was placed in 300g of crushed ice, stirred well, and the precipitated solid, -5 ° C frozen standing for 2 hours the above.

[0152] filtered, washed with water to pH 8-9, drained, and dried to give piperidinol (XVH) 15g, yield 94%, mp 137-144 ° C, ash content <5%.

[0153] Example 2

[0154] (a) 3- (4-fluorobenzoyl) propionic acid (2) (the acid) is prepared:


Figure CN106187863AD00251

[0156] The reaction flask equipped with a mechanical stirrer, a condenser, a thermometer three 500ml, was added 17.1g (0.171mol) of succinic anhydride, l〇5g (1 · 09mol) fluorobenzene, stirred and dissolved. Added in one portion 60g (0 · 306mol) in dry wrong trichloride, stirring, the reaction was stirred at 100 ° C for 2 hours, at a concentration of 10% by weight hydrochloric acid 165ml exploded 30 minutes;

[0157] Other embodiments with Example 1, the product, 111.? 105-107 ° (:, this step a yield of 81.5%, 46.7% overall yield.


  1. ^ van Praag HM, Schut T, Dols L, van Schilfgaarden R., Controlled trial of penfluridol in acute psychosis, Br Med J. 1971 December 18;4(5789):710-3
  2. ^ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, Van Nueten JM, Schaper WK., The pharmacology of penfluridol (R 16341) a new potent and orally long-acting neuroleptic drug, Eur J Pharmacol. 1970 July 15;11(2):139-54
  3. Jump up to:a b Soares, B; Silva de Lima, M (2006). “Penfluridol for schizophrenia”Cochrane Database of Systematic Reviews2: CD002923.pub2. doi:10.1002/14651858.CD002923.pub2.

Further reading

  • Benkert O, Hippius H.: Psychiatrische Pharmakotherapie, Springer-Verlag, 1976, 2. Auflage. ISBN3-540-07916-5
  • R Bhattacharyya, R Bhadra U Roy, S Bhattacharyya, J Pal S Sh Saha – Resurgence of Penfluridol:Merits and Demerits, Eastern Journal of Psychiatry, January-June 2015 vol 18, Issue 1 p 23 –29
Clinical data
AHFS/ International Drug Names
ATC code
CAS Number
CompTox Dashboard(EPA)
ECHA InfoCard 100.043.689Edit this at Wikidata
Chemical and physical data
Formula C28H27ClF5NO
Molar mass 523.965 g·mol−1
3D model (JSmol)

/////////Penfluridol, Antipsychotic, SemapMicefalLongoperidol, MCN-JR-16,341, R 16,341, MCN-JR-16,341 / R 16,341, 



ChemSpider 2D Image | elacridar | C34H33N3O5


C34H33N3O5, 563.6 g/mol

143664-11-3 [RN]
143851-84-7 (maleate salt(1:1))
143851-98-3 (monoHCl)
4-Acridinecarboxamide, N-[4-[2-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)ethyl]phenyl]-9,10-dihydro-5-methoxy-9-oxo-[ACD/Index Name]



Elacridar (GF120918)

GF-120918A (HCl)

GlaxoSmithKline  (previously  Glaxo Wellcome ) was developing elacridar, an inhibitor of the multidrug resistance transporter BCRP (breast cancer resistant protein), as an oral bioenhancer for the treatment of solid tumors.

Elacridar is an oral bioenhancer which had been in early clinical trials at GlaxoSmithKline for the treatment of cancer, however, no recent development has been reported. It is a very potent inhibitor of P-glycoprotein, an ABC-transporter protein that has been implicated in conferring multidrug resistance to tumor cells.


The condensation of 2-(4-nitrophenyl)ethyl bromide with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline by means of K2CO3 and KI in DMF at 100 C gives 6,7-dimethoxy-2-[2-(4-nitrophenyl)ethyl]-1,2,3,4-tetrahydroisoquinoline,

Which is reduced with H2 over Pd/C in ethanol to yield the corresponding amine . Finally, this compound is condensed with 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid  by means of DCC and HOBt in DMF to afford the target carboxamide.

The intermediate 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acidhas been obtained as follows: The condensation of 2-amino-3-methoxybenzoic acid  with 2-bromobenzoic acid  by means of K2CO3 and copper dust give the diphenylamine , which is cyclized to the target acridine Elacridar by means of POCl3 in refluxing acetonitrile.



Deuterated analogs of elacridar as P-gp/BCRP inhibitor by preventing efflux useful for treating cancer.

Elacridar, previously referred to as GF120918, is a compound with the structure of 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1 ,2,3,4-tetrahydro- 6,7-dimethoxy-2-isoquinolinyl)ethyl] phenyl]-4-acridine-carboxamide or, as sometimes written, N-4-[2-(1 ,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy- 9-oxo-4-acridine carboxamide. Elacridar was originally described as a P-gp selective inhibitor but is now recognized as a dual P-gp/BCRP inhibitor. (Matsson P, Pedersen JM, Norinder U, Bergstrom CA, and Artursson P 2009 Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs. Pharm Res 26:1816-1831 ).

003 Elacridar has been examined with some success both in vitro and in vivo as a P-gp and BCRP inhibitor. By way of example, in cancer patients, coadministration of elacridar with therapeutic agents such as paclitaxel (P-gp substrate) and topotecan (BCRP substrate) improved their oral absorption – presumably by preventing efflux into the intestinal lumen by P-gp/BCRP pumps located in the Gl tract. Similarly, in rodents, elacridar has been coadministered with some success with pump substrates such as morphine, amprenavir, imatinib, dasatinib, gefitinib, sorafenib, and sunitinib to increase drug levels in the brain (by blocking efflux mediated by P-gp and BCRP at the blood brain barrier). A summary of some of these studies can be found in a study report by Sane et al. (Drug Metabolism And Disposition 40:1612-1619, 2012).

004 Administration of elacridar has several limitations. By way of example, elacridar has unfavorable physicochemical properties; it is practically insoluble in water, making it difficult to formulate as, for example, either an injectable or oral dosage form. Elacridar’s poor solubility and high lipophilicity result in dissolution rate-limited absorption from the gut lumen.

005 A variety of approaches have been pursued in order to increase efficacy of elacridar. For example, United States Patent Application Publication 20140235631 discloses a nanoparticle formulation in order to increase oral bioavailability.

006 Sane et al. (Journal of Pharmaceutical Sciences, Vol. 102, 1343-1354 (2013)) report a micro-emulsion formulation of elacridar to try and overcome its dissolution-rate-limited bioavailability.

007 Sawicki et al. (Drug Development and Industrial Pharmacy, 2017 VOL. 43, NO. 4, 584-594) described an amorphous solid dispersion formulation of freeze dried elacridar hydrochloride-povidone K30-sodium dodecyl sulfate. However, when tested in healthy human volunteers, extremely high doses (e.g. 1000 mg) were required to achieve a Cmax of 326 ng/ml. (Sawicki et al. Drug Deliv. and Transl.

Res. Published online 18 Nov 2016).

008 Montesinos et al. (Mol Pharm. 2015 Nov 2; 12(11 ):3829-38) attempted several PEGylated liposome formulations of elacridar which resulted in a partial increase in half life, but without an increase in efficacy when co-administered with a therapeutic agent.

009 Because of the great unpredictability in the art and poor correlations in many cases between animal and human data, the value of such formulation attempts await clinical trial.

0010 Studies of the whole body distribution of a microdose of 11C elacridar after intravenous injection showed high level accumulation in the liver (Bauer et al. J Nucl Med. 2016;57:1265-1268). This has led some to suggest that systemic levels of elacridar are also substantially limited by clearance in the liver.

0011 A potentially attractive strategy for improving metabolic stability of some drugs is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the rate of formation of inactive metabolites by replacing one or more hydrogen atoms with deuterium atoms.

Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the absorption, distribution, metabolism, excretion and/or toxicity (‘ADMET’) properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

0012 Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, M I et al, J Pharm Sci, 1975, 64:367-91 ; Foster, A B, Adv Drug Res 1985, 14:1 -40 (“Foster”); Kushner, D J et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, Curr Opin Drug Discov Devel, 2006, 9:101 -09 (“Fisher”)). The results have been variable and unpredictable. For some compounds, deuteration indeed caused decreased metabolic clearance in vivo. For others, no change in metabolism was observed. Still others demonstrated increased metabolic clearance. The great unpredictability and variability in deuterium effects has led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting metabolism (see Foster at p. 35 and Fisher at p. 101 ).

0013 The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991 , 34, 2871 -76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

0014 Considering elacridar’s challenging physicochemical and ADMET properties in humans, in spite of recent formulation advancements, there remains a need in the art for elacridar analogs that can achieve higher, less variable levels in the systemic circulation, at the blood-brain barrier, and elsewhere to optimize efflux inhibition.

Example 1 : Synthesis of Instant Analogs and Compositions

00179 This example demonstrates a synthetic method for making elacridar analogs, deuterium substitutions based upon the deuteration of the starting compounds. The synthesis and the analog numbers refer to Figure 4.

00180 Step 1

00181 A 12L three-neck flask was charged with compound 1 (270.5 g, 1.618 mol), compound 2 (357.8 g, 1.78 mol, 1.1 eq.), K2C03 (447 g, 3.236 mol, 2.0 eq), Cu (20.6 g, 0.324 mol, 0.2 eq.) and ethanol (2.7 L) and the resulting mixture was heated to reflux under nitrogen for 1 hour. The reaction mixture was cooled to room

temperature after the reaction progress was checked with LC-MS. Water (2.7 L) was added and the mixture was filtered through a pad of Celite. The Celite was washed with water (1.35L) and the combined filtrate was adjusted to pH~2 by addition of concentrated HCI (~410 mL) over 15 min. The resulting suspension was stirred at 10°C for 1.5 hours and the solid was filtered, washed with water (2.7 L) and dried at 45°C using a vacuum oven for 2 days to give compound 3 (465 g, ~100%) as a yellow solid.

00182 Step 2

00183 A suspension of compound 3 (498 g, 1.734 mol) in acetonitrile (4.0 L) was heated to reflux under stirring. To the suspension was added POCb (355.5 mL,

3.814 mol, 2.2 eq.) drop-wise over 2h. The mixture was heated at reflux for 2.5h and then cooled to 30 °C. To the mixture was slowly added water (3.0 L) and the resultant thick slurry was heated to reflux for 1 5h. The slurry was cooled to 10 °C and filtered. The solid was washed with water (2 X 1.0 L), acetonitrile (2 X 1.0 L) and dried using a vacuum oven overnight at 45 °C to afford compound 4 (426 g, 91.3%) as a yellow solid.

00184 Step 3:

00185 A 12L three-neck flask was charged with compound 5 (475g, 2.065 mol), compound 6 (474.8g, 2.065 mol), K2C03 (314g, 2.273 mol), Kl (68.6g, 0.413 moL) and DMF (2.5L) and the resulting mixture was heated to 70 °C and stirred for 2.5 hours. After LC-MS showed that the reaction was complete, the mixture was cooled to 50 °C and methanol (620 ml_) was added. Then the mixture was cooled to 30 °C and water (4.75 L) was added. The resulting suspension was cooled to 10 °C and for 1 hour. The solid was filtered, washed with water (2 X 2.5 L) and air dried for 2 days to afford the compound 7 (630 g, 89.1 %) as a yellow solid.

00186 Step 4

00187 To a solution of compound 7 (630 g, 1.84 mol) in THF/ethanol (8 L at 1 :1 ) was added Pd/C (10%, 50% wet, 30 g). The mixture was stirred under an

atmosphere of hydrogen (1 atm, balloon) at 15-20 °C for 4h. The reaction mixture was filtered through a pad of Celite and the pad was washed with TFIF (1.0 L). The filtrate was concentrated to 3 volumes under vacuum and hexanes (4.0 L) was added. The resulting slurry was cooled to 0 °C and stirred for 1 h. The solid was filtered and washed with hexanes (2 X 500 ml_) and air dried overnight to afford the compound 8 (522 g, 90.8%) as an off -white solid.

00188 Step 5

00189 A 5L three-neck flask was charged with compound 4 (250 g, 0.929 mol, 1 eq.), compound 8 (290 g, 0.929mol, 1 eq.) and DMF (2.5 L) and the resulting mixture was stirred at room temperature until it became a clear solution. To the solution was added TBTU (328 g, 1.021 mol, 1.1 eq.), followed by triethylamine (272 ml_, 1.95 mol, 2.1 eq.) and the resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was poured slowly into water (7.5 L) with stirring and the resulting suspension was stirred for 1 hour at room temperature. The solid was filtered and washed with water (2 X 7 L). The solid thus obtained was dried using a vacuum oven at 50 °C for two days and 509.0 g (97.3%) of compound 9 was obtained as yellow solid.

00190 Step 6

00191 300.0 g (0.532 mol) of compound 9 was suspended in acetic acid (1.2 L) and heated to 70 °C. The resultant solution was hot filtered and heated to 70°C again. Preheated ethanol (70 °C, 3.6 L) was then added. To this solution was added concentrated HCI (66.0 ml_, 0.792 mol, 1.5 eq.) dropwise over 30 min. The resulting solution was stirred at 70°C until crystallization commenced (~about 20 min). The suspension was cooled to room temperature over 3h, filtered, washed with ethanol (2 X 1.8 L) and dried using a vacuum oven at 60°C over the weekend to afford compound 10 (253.0 g, 79.2%) as a brown solid.

Example 2 Manufacture of a Deuterated Elacridar analog EE60.

00192 EE60 is synthesized by the procedure shown in Figure 4 and as continued in Figure 5.

00193 The structure of EE60 is confirmed as follows: Samples of 5 pi are measured using an LC system comprising an UltiMate 3000 LC Systems (Dionex, Sunnyvale, CA) and an 2996 UV diode array detector (Waters). Samples are injected on to a 100 x 2mm (ID) 3.5 pm ZORBAX Extend-C18 column (Agilent, Santa Clara, CA). Elution is done at a flow rate of 0.4 mL/min using a 5 minute gradient from 20% to 95% B (mobile phase A was 0.1 % FICOOFI in water (v/v) and mobile phase B was methanol). 95% B is maintained for 1 min followed by re-equilibration at 20% B. Chromeleon (v6.8) is used for data acquisition and peak processing.

Example 3: Manufacture of a Deuterated Elacridar analog EE59

00194 EE59 was synthesized by the procedure shown in Figure 6.

00195 The resulting yellowish brown precipitate was removed by filtration and the filter cake was dried overnight (72 mg). Analysis of the filter cake by LCMS indicated the presence of a single peak at multiple wavelengths (215 nm, 220 nm, 254 nm,

280 nm); each peak confirmed the presence of the desired product (LC retention time, 5.3 min; m/z = 575 [(M+FI)+]).

00196 1H NMR of EE598 revealed 1H NMR (400 MHz, DMSO-d6) d 12.3 ( s , 1H), 10.6 (s, 1H), 8.51-8.46 (m, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.45-7.38 (m, 2H), 7.32-7.25 (m, 3H), 6.66 (d, J = 6.8 Hz, 2H), 3.62 (s, 2H), 2.86 (t, J = 6.8 Hz, 2H), 2.66 (m, 4H).

Example 4: Demonstration of superior properties of instant analogs and compositions: in vivo ADMET.

00197 Pharmacologic studies are performed according to Ward KW et al (2001 Xenobiotica 317783-797) and Ward and Azzarano (JPET 310:703-709, 2004).

Briefly, instant analogs are administered solutions in 10% aqueous polyethylene glycol-300 (PEG-300) or 6% Cavitron with 1 % dimethyl sulfoxide, or as well triturated suspensions in 0.5% aqueous HPMC containing 1 % Tween 80. Blood samples are collected at various times up to 48 h after drug administration; plasma samples are prepared and at “70°C until analysis.

00198 Mice. Instant analogs are administered to four groups of animals by oral gavage (10 ml/kg dose volume). Three groups receive instant analogs as a suspension at 3, 30, or 300 mg/kg, and the fourth group receive instant analogs as a solution in Cavitron at 3 mg/kg. Blood sampling in mice is performed via a tail vein at 0.5, 1 , 2, 4, 8, 24, and 32 h postdose.

00199 Rats. A total of seven groups of animals receive instant analogs by oral gavage (10 ml/kg). Three groups receive instant analogs as a suspension at 3, 30, or 300 mg/kg, and a fourth and fifth group each receive instant analogs as a solution in Cavitron or PEG-300, respectively, at 3 mg/kg. A sixth and seventh group of rats with indwelling hepatic portal vein catheters receive instant analogs by oral gavage (10 ml/kg) as a suspension at 3 or 30 mg/kg, respectively. Blood sampling in rats are performed via a lateral tail vein; samples are also obtained from the hepatic portal vein catheter. Blood samples are obtained before dosing and at 5, 15, 30, and 45 min, and 1 ,1.5, 2, 3, 4, 6, 8, 10, 24, and 32 h postdose.

00200 Dogs. Dogs receive instant analogs by lavage (4 ml/kg) on three separate occasions with dosages at 3 and 30 mg/kg as a suspension and 3 mg/kg as a solution in Cavitron. Blood samples are obtained from a cephalic vein and from the hepatic portal vein catheter before dosing and at 5, 15, 30, and 45 min and 1 , 1.5, 2, 3, 4, 6, 8, 10, 24, 32, and 48 h postdose.

00201 Monkeys. Monkeys receive instant analogs by oral gavage (8 ml/kg dose volume) on three separate occasions at dosages of 3 and 30 mg/kg as a suspension and 3 mg/kg as a solution in Cavitron. Blood samples are obtained from a femoral vein via an indwelling catheter and from the hepatic portal vascular access port

before dosing and at 5, 15, and 30 min and 1 , 1.5, 2, 4, 6, 8, 10, 24, 32, and 48 h postdose.

00202 Humans. Healthy volunteers receive instant analogs orally at doses ranging from 25 mg to 1000 mg. Blood samples are obtained and analyzed for analog concentrations at 0, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 2 hr, 4 hr, 6hr, 8 hr, 12 hr, 24 hr, and 48 h after administration .

Analytical Methods

00203 Instant analogs are isolated from samples by precipitation with acetonitrile and quantified by LC/MS/MS coupled with an atmospheric pressure chemical ionization interface (475°C). Internal standards [in acetonitrile/10 mM ammonium formate, pH 3.0; 95:5 (v/v)] are added to 50 pi samples and vortexed and centrifuged for 30 min at 4000 rpm. The supernatants are injected onto the LC/MS/MS system using an HTS PAL autosampler (CTC Analytics, Zwingen, Switzerland) coupled to an Aria TX2 high-throughput liquid chromatographic system using turbulent flow technology (Cohesive Technologies, Franklin, MA) in focus mode. The mobile phase consists of a mixture of 0.1 % formic acid in water and 0.1 % formic acid in

acetonitrile. The turbulent flow column is a 0.5 X 50-mm Cyclone P column

(Cohesive Technologies) in series to a 2 X 20 mm, 4 pm Polar RP (Phenomenex, Torrance, CA) analytical column. Positive-ion multiple reaction monitoring is used for the detection of instant analogs and internal standard and the selected precursor and product ions are mlz 564 and 252, respectively. Using a (1/x) weighted linear regression analysis of the calibration curve, linear responses in analyte/internal standard peak area ratios are observed for instant analog concentrations ranging from 2 to 10,000 ng/ml.

00204 Alternatively, useful analytical methods to demonstrate the surprising and superior properties of the instant elacridar analogs are the methods as described by Stokvis et al, J Mass Spectr 2004: 39: 1122-1130.



claiming nano-particle composition comprising breast cancer resistance protein inhibitor (eg elacridar).  Family member of the elacridar


J Med Chem 1995, 38(13): 2418


Product PATENT WO9212132



NMR includes d 2.60-2.95 (m,8H,CH2); 3.58 (s,2H,N–CH2 –Ph); 3.72 (s,6H,OMe); 4.05 (s,3H,OMe acridone); 6.78 (2s,2H,Ar.isoquinoline), 7.20-7.88 (m,8H,Ar.), 8.48 (t,2H,H1 and H8 acridone), 10.60 (s, 1H,CONH), 12.32 (s, 1H,NH acridone)

///////////Elacridar, GF-120918, GG-918 , GW-120918, GW-918, GF-120918A (HCl), solid tumors, GSK, GLAXO




Molecular Weight


CAS Number, 1187575-76-3




C32H38ClN3O2, 532.1 g/mol

CAS 603148-36-3




TTP-488; PF-04494700


MOA:RAGE inhibitor

Indication:Alzheimer’s disease (AD)

Status:Phase III (Active), Dementia, Alzheimer’s type
Company:vTv Therapeutics (Originator)


Azeliragon is in phase III clinical for the treatment of Alzheimer’s type dementia.

Azeliragon was originally by TransTech Pharma (now vTv Therapeutics), then licensed to Pfizer in 2006.

Pfizer discontinued the research in 2011, now vTv Therapeutics continues the further reaserch.

vTv Therapeutics  (previously TransTech Pharma) is developing azeliragon, an orally active antagonist of the receptor for advanced glycation end products (RAGE), for the treatment of Alzheimer’s disease (AD) in patients with diabetes.  In June 2019, this was still the case .

Azeliragon was originally developed at TransTech Pharma. In September 2006, Pfizer entered into a license agreement with the company for the development and commercialization of small- and large-molecule compounds under development at TransTech. Pursuant to the collaboration, Pfizer gained exclusive worldwide rights to develop and commercialize TransTech’s portfolio of RAGE modulators, including azeliragon.


1. WO03075921A2.

2. US2008249316A1.

US 20080249316

VTV Therapeutics

Azeliragon (TTP488) is an orally bioavailable small molecule that inhibits the receptor for advanced glycation endproducts (RAGE). A Phase 2 clinical trial to evaluate azeliragon as a potential treatment of mild-AD in patients with type 2 diabetes is ongoing.  The randomized, double-blind, placebo-controlled multicenter trial is designed as sequential phase 2 and phase 3 studies operationally conducted under one protocol. For additional information on the study, refer to NCT03980730 at

RAGE is an immunoglobulin-like cell surface receptor that is overexpressed in brain tissues of patients with AD. The multiligand nature of RAGE is highlighted by its ability to bind diverse ligands such as advanced glycation end-products (AGEs), linked to diabetic complications and β-amyloid fibrils, a hallmark of AD. The association between type 2 diabetes and AD is well documented. A linear correlation between circulating hemoglobin A1c (HbA1c) levels and cognitive decline has been demonstrated in the English Longitudinal Study of Ageing.



Novel crystalline forms of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine and its salt ( azeliragon ) (deignated as forms III and IV) as RAGE inhibitors useful for treating  psoriasis, rheumatoid arthritis and Alzheimer’s disease.

The Receptor for Advanced Glycation Endproducts (RAGE) is a member of the immunoglobulin super family of cell surface molecules. Activation of RAGE in different tissues and organs leads to a number of pathophysiological consequences. RAGE has been implicated in a variety of conditions including: acute and chronic inflammation (Hofmann et al., Cell 97:889-901 (1999)), the development of diabetic late complications such as increased vascular permeability (Wautier et al., J. Clin. Invest. 97:238-243 (1995)), nephropathy (Teillet et al., J. Am. Soc. Nephrol. 11 : 1488- 1497 (2000)), atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al., Diabetologia 42:603-607 (1999)). RAGE has also been implicated in Alzheimer’s disease (Yan et al., Nature 382: 685-691 , (1996)), erectile dysfunction, and in tumor invasion and metastasis (Taguchi et al., Nature 405: 354-357, (2000)).

Binding of ligands such as advanced glycation endproducts (AGEs), S100/calgranulin/EN-RAGE, b-amyloid, CML (Ne-Carboxymethyl lysine), and amphoterin to RAGE has been shown to modify expression of a variety of genes. For example, in many cell types interaction between RAGE and its ligands generates oxidative stress, which thereby results in activation of the free radical sensitive transcription factor NF-kB, and the activation of NF-kB regulated genes, such as the cytokines IL- 1 b, TNF- a, and the like. In addition, several other regulatory pathways, such as those involving p21 ras.

MAP kinases, ERK1 and ERK2, have been shown to be activated by binding of AGEs and other ligands to RAGE. In fact, transcription of RAGE itself is regulated at least in part by NF-kB. Thus, an ascending, and often detrimental, spiral is fueled by a positive feedback loop initiated by ligand binding. Antagonizing binding of physiological ligands to RAGE, therefore, is our target, for down-regulation of the pathophysiological changes brought about by excessive concentrations of AGEs and other ligands for RAGE.

Pharmaceutically acceptable salts of a given compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, melting point, crystal shape, compaction behavior, flow properties, and/or solid state stability. These differences affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Although U.S. Patent No. 7,884,219 discloses Form I and Form II of COMPOUND I as a free base, there is a need for additional drug forms that are useful for inhibiting RAGE activity in vitro and in vivo, and have properties suitable for large-scale manufacturing and formulation. Provided herein








Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics

Presentations and Posters

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics

///////////Azeliragon, psoriasis, rheumatoid arthritis, Alzheimer’s disease, TTP-488,  PF-04494700, RAGE inhibitors, TransTech Pharma, PHASE 3, Dementia, Alzheimer’s type,


Afamelanotide, アファメラノチド , афамеланотид , أفاميلانوتيد , 阿法诺肽 ,


2D chemical structure of 75921-69-6

ChemSpider 2D Image | Afamelanotide | C78H111N21O19

Click here for structure editor


RN: 75921-69-6

Molecular Formula, C78-H111-N21-O19, Molecular Weight, 1646.8629


  • 75921-69-6
  • CUV1647
  • CUV-1647

alpha-Melanotropin, 4-L-norleucine-7-D-phenylalanine-

Prevention of Phototoxicity in Adults with Erythropoietic Protoporphyria (EPP)



афамеланотид [Russian] [INN]
أفاميلانوتيد [Arabic] [INN]
阿法诺肽 [Chinese] [INN]

Observations suggest that afamelanotide has beneficial effects in patients with erythropoietic protoporphyria, induces epidermal melanin formation.


Lensing, Cody J. et alFrom Journal of Medicinal Chemistry, 62(1), 144-158; 2019


oct 2019

FDA approves first treatment to increase pain-free light exposure in patients with a rare disorder

The U.S. Food and Drug Administration today granted approval to Scenesse (afamelanotide) to increase pain-free light exposure in adult patients with a history of phototoxic reactions (damage to skin) from erythropoietic protoporphyria.

For patients who are suffering from erythropoietic protoporphyria, a rare disorder, exposure to light may be extremely painful. Prior to today’s approval, there were no FDA-approved treatments to help erythropoietic protoporphyria patients increase their light exposure,” said Julie Beitz, M.D., director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III. “Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible.”

Erythropoietic protoporphyria is a rare disorder caused by mutations leading to impaired activity of ferrochelatase, an enzyme involved in heme production. Heme is an important component in hemoglobin, the oxygen carrying molecule in red blood cells. The decrease in ferrochelatase activity leads to an accumulation of protoporphyrin IX (PPIX) in the body. Light reaching the skin can react with PPIX causing intense skin pain and skin changes, such as redness and thickening. Scenesse (afamelanotide), a melanocortin-1 receptor (MC1-R) agonist, increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources.  It is an implant that is administered subcutaneously (inserted under the skin).

The efficacy of Scenesse was established in two parallel group clinical trials with patients with erythropoietic protoporphyria who received Scenesse or placebo form of the implant subcutaneously every two months. The first clinical trial enrolled 93 subjects, of whom 48 received Scenesse, and were followed for 180 days. The primary endpoint was the total number of hours over 180 days spent in direct sunlight between 10 a.m. and 6 p.m. on days with no pain. The median total number of hours over 180 days spent in direct sunlight between 10 a.m. and 6 p.m. on days with no pain was 64 hours for patients receiving Scenesse and 41 hours for patients taking placebo.

The second clinical trial enrolled 74 patients, of whom 38 received Scenesse, and were followed for 270 days. The primary endpoint was the total number of hours over 270 days spent outdoors between 10 am and 3 pm on days with no pain for which “most of the day” was spent in direct sunlight. The analysis did not include sun exposure on days patients reported spending time in a combination of both direct sunlight and shade. The median total number of hours over 270 days spent outdoors between 10 am and 3 pm on days with no pain for which “most of the day” was spent in direct sunlight was six hours for patients receiving Scenesse and 0.75 hours for patients receiving placebo.

Scenesse’s most common side effects are implant site reaction, nausea, oropharyngeal (part of the throat just behind the mouth, where the oral cavity starts) pain, cough, fatigue, skin hyperpigmentation, dizziness, melanocytic nevus (moles), respiratory tract infection, somnolence (feeling drowsy), non-acute porphyria (build-up of normally occurring molecules created during heme production) and skin irritation. Scenesse should be administered by a health care professional who is proficient in the subcutaneous implantation procedure and has completed the applicant-provided training. Scenesse may induce skin darkening, and a full body skin examination is recommended for patients twice a year. In addition, patients are encouraged to maintain sun protection measures during treatment with Scenesse to prevent phototoxic reactions related to erythropoietic protoporphyria.

The FDA granted this application Priority Review designation. Scenesse also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.The approval of Scenesse was granted to Clinuvel.

For more information:

Afamelanotide (melanotan ICUV1647; brand name Scenesse)[2] is a synthetic peptide and analogue of α-melanocyte stimulating hormone used to prevent skin damage from the sun in people with erythropoietic protoporphyria in Europe since January 2015. It is administered as an implant that is placed under the skin; the implant lasts for two months.

It is under development in other skin disorders in several jurisdictions. It causes skin to turn darker by causing the skin to make more melanin.

It was discovered at University of Arizona and initially developed there as a sunless tanning agent; the Australian company Clinuvel conducted further clinical trials in that and other indications, and brought the drug to market.

Unlicensed and untested powders sold as “melanotan” are found on the Internet marketed for tanning and other purposes, and multiple regulatory bodies have warned consumers that the peptides may be unsafe and ineffective.

Medical use

Afamelanotide is used in Europe to prevent phototoxicity in adults with erythropoietic protoporphyria (EPP).[1] It is an implant that is injected and placed under the skin; an implant lasts two months.[1]

People who have severe liver disease, liver impairment, or kidney impairment, should not use this drug. Pregnant women should not take it, and women who are active sexually should use contraception while they are taking it. It is not known if afamelanotide is secreted in breast milk.[1]

Adverse effects

Very common (up to 10% of people) adverse effects in people with EPP include headache and nausea. Common (between 1% and 10%) adverse effects include back pain, upper respiratory tract infections, decreased appetite, migraine, dizziness, weakness, fatigue, lethargy, sleepiness, feeling hot, stomach pain, diarrhea, vomiting, flushing and red skin, development of warts, spots, and freckles, itchy skin, and reactions at the injection site. There are many uncommon (less than 1%) adverse effects.[1]


Afamelanotide is thought to cause skin to darken by binding to the melanocortin 1 receptor which in turn drives melanogenesis.[1]

Afamelanotide has a half-life of 30 minutes. After the implant is injected, most of the drug is released within the first 2 days, with 90% released by the fifth day. By the tenth day no drug is detectable in plasma.[1]

Its metabolites, distribution, metabolism and excretion were not understood as of 2017.[1]


The amino acid sequence is Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, and it is additionally known as [Nle4,D-Phe7]-α-MSH, which is sometimes abbreviated as NDP-MSH or NDP-α-MSH. Afamelanotide is the International Nonproprietary Name.[3]


The role of α-MSH in promoting melanin diffusion has been known since the 1960s.[4] In the 1980s, scientists at University of Arizona began attempting to develop α-MSH and analogs as potential sunless tanning agents, and synthesized and tested several analogs, including melanotan-I.[5]

To pursue the tanning agent, melanotan-I was licensed by Competitive Technologies, a technology transfer company operating on behalf of University of Arizona, to an Australian startup called Epitan,[6][5] which changed its name to Clinuvel in 2006.[7]

Early clinical trials showed that the peptide had to be injected about ten times a day due to its short half-life, so the company collaborated with Southern Research in the US to develop a depot formulation that would be injected under the skin, and release the peptide slowly. This was done by 2004.[6]

As of 2010, afamelanotide was in Phase III trials for erythropoietic protoporphyria and polymorphous light eruption, and was in Phase II trials for actinic keratosis and squamous cell carcinoma, and had been trialled in phototoxicity associated with systemic photodynamic therapy and solar urticaria.[8] Clinuvel had also obtained orphan drug status for afamelanotide in the US and the EU by that time.[8]

In May 2010 the Italian Medicines Agency (AIFA, or Agenzia Italiana del Farmaco) approved afamelanotide as a treatment for erythropoietic protoporphyria.[9]

In January 2015 afamelanotide was approved by the EMA in Europe for the treatment of phototoxicity in people with EPP.[1]

Society and culture


A number of products are sold online and in gyms and beauty salons as “melanotan” or “melanotan-1” which discuss afamelanotide in their marketing.[10][11] [12]

The products are not legal in any jurisdiction and are dangerous.[13][14][15][16]

Starting in 2007 health agencies in various counties began issuing warnings against their use.[17][18][19][20] [21][22]


Sawyer T K; Sanfilippo P J; Hruby V J; Engel M H; Heward C B; Burnett J B; Hadley M E

  • From Proceedings of the National Academy of Sciences of the United States of America (1980), 77(10), 5754-8.

2 Journal of Medicinal Chemistry (1982), 25(9), 1022-7.

3 Journal of medicinal chemistry (1984), 27(11), 1406-10.

4 Journal of Medicinal Chemistry (2019), 62(1), 144-158

5 Journal of Medicinal Chemistry (2018), 61(17), 7729-7740.

6 Journal of medicinal chemistry (2017), 60(2), 805-813.


US 4457864


  1. Jump up to:a b c d e f g h i “Scenesse: Summary of Product Characteristics” (PDF). EMA. 27 January 2016. Retrieved 6 April 2017. For updates see EMA Index page
  2. ^ “Afamelanotide”. AdisInsight. Retrieved 6 April 2017.
  3. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF)World Health Organization. 2009. Retrieved 2009-03-02.
  4. ^ Baker, BI (31 May 1993). “The role of melanin-concentrating hormone in color change”. Annals of the New York Academy of Sciences680: 279–89. doi:10.1111/j.1749-6632.1993.tb19690.xPMID 8390154.
  5. Jump up to:a b Hadley, ME; Dorr, RT (April 2006). “Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization”. Peptides27 (4): 921–30. doi:10.1016/j.peptides.2005.01.029PMID 16412534.
  6. Jump up to:a b “EpiTan focuses on Melanotan, a potential blockbuster”The Pharma Letter. 1 November 2004.
  7. ^ “Epitan changes name to Clinuvel, announces new clinical program”LabOnline. 27 February 2006.
  8. Jump up to:a b Dean, Tim (3 May 2010). “Biotechnology profile: Bright future for Clinuvel (ASX:CUV)”Australian Life Scientist. Archived from the original on 6 April 2017.
  9. ^ “GAZZETTA UFFICIALE: SOMMARIO”Agenzia Nazionale Stampa Associata. 2010. Retrieved 2010-05-17.
  10. ^ “Believe It Or Not ‘Tanorexia’ A Very Real Problem”WCBS-TVCBS. 2009-05-20. Archived from the original on May 21, 2009. Retrieved 2009-07-23.
  11. ^ “Fools Gold”Cosmopolitan (Australia). 2009-06-14. Retrieved 2009-07-25.
  12. ^ Madrigal, Alexis (2009-01-29). “Suntan Drug Greenlighted for Trials”WiredArchivedfrom the original on 5 May 2009. Retrieved 2009-04-11.
  13. ^ “Tanning drug a health risk”Herald Sun. 2009-10-31. Retrieved 2009-10-31.
  14. ^ Ewan A Langan; Z. Nie; Lesley E Rhodes (June 2010). “Melanotropic peptides: More than just “Barbie drugs” and “sun tan jabs?“. British Journal of Dermatology163 (3): 451–5. doi:10.1111/j.1365-2133.2010.09891.xPMID 20545686.
  15. ^ Ewan A Langan; Denise Ramlogan; Lynne A Jamieson; Lesley E Rhodes (January 2009). “Change in moles linked to use of unlicensed “sun tan jab“. BMJ338: b277. doi:10.1136/bmj.b277PMID 19174439.
  16. ^ “Risky tan jab warnings ‘ignoredBBC. 2009-02-18. Archived from the original on 21 February 2009. Retrieved 2009-03-04.
  17. ^ “Warning against the product Melanotan”Danish Medicines Agency. 2008. Retrieved 2008-08-11.
  18. ^ Tan jab” is an unlicensed medicine and may not be safe”MHRA. 2008. Archived from the original on 2014-12-05. Retrieved 2008-11-17.
  19. ^ “US Lab Research Inc Warning letter”. U.S. Food and Drug Administration. 2009-01-29. Archived from the original on 10 July 2009. Retrieved 2009-07-23.
  20. ^ “Melanotan Powder for Injection”Notice Information: – Warning – 27 February 2009Irish Medicines Board. 2009. Retrieved 2009-02-02.
  21. ^ “Legemiddelverket advarer mot bruk av Melanotan”. Norwegian Medicines Agency. 2007-12-13. Archived from the original on 17 April 2009. Retrieved 2009-03-11.
  22. ^ “Melanotan – farlig og ulovlig brunfarge”Norwegian Medicines Agency. 2009-01-23. Archived from the original on 17 April 2009. Retrieved 2009-03-11.
Clinical data
Pronunciation /ˌæfəmɛˈlæntd/ (About this soundlisten)
Trade names Scenesse
Synonyms Melanotan; Melanotan-1; Melanotan I; CUV1647; EPT1647; NDP-MSH; NDP-α-MSH; [Nle4,D-Phe7]α-MSH
AHFS/ UK Drug Information
License data
Routes of
S.C.I.M.I.V.subcutaneous implantintranasal
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Elimination half-life 30 minutes[1]
CAS Number
PubChem CID
CompTox Dashboard (EPA)
Chemical and physical data
Formula C78H111N21O19
Molar mass 1646.845 g/mol g·mol−1
3D model (JSmol)

/////////////fda 2019, Scenesse, afamelanotide,  pain-free light exposure,  erythropoietic protoporphyria, アファメラノチド , афамеланотид أفاميلانوتيد 阿法诺肽 

Afamelanotide acetate [USAN]

MW: 1706.9145

2D chemical structure of 1566590-77-9

Valacyclovir HCl


ChemSpider 2D Image | Valaciclovir | C13H20N6O4


124832-26-4 [RN]
2-[(2-amino-6-hydroxy-9H-purin-9-yl)methoxy]ethyl L-valinate
2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl L-valinate [ACD/IUPAC Name]
2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl-L-valinat [German] [ACD/IUPAC Name]
2-{[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]oxy}ethyl L-valinate
L-Valinate de 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)méthoxy]éthyle [French] [ACD/IUPAC Name]
L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
L-valine ester with 9-[(2-hydroxyethoxy)methyl]guanine
L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester [ACD/Index Name]
L-valine, 2-[(2-amino-6-hydroxy-9H-purin-9-yl)methoxy]ethyl ester
CAS Registry Number: 124832-26-4
CAS Name: L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
Additional Names: L-valine ester with 9-[(2-hydroxyethoxy)methyl]guanine; valaciclovir; ValACV
Molecular Formula: C13H20N6O4
Molecular Weight: 324.34
Percent Composition: C 48.14%, H 6.22%, N 25.91%, O 19.73%
Literature References: L-Valine ester prodrug of acyclovir, q.v. Prepn: T. A. Krenitsky et al., EP 308065; L. M. Beauchamp, US4957924 (1989, 1990 both to Wellcome). Evaluation as prodrug: L. M. Beauchamp et al., Antiviral Chem. Chemother. 3, 157 (1992). Clinical pharmacokinetics: S. Weller et al., Clin. Pharmacol. Ther. 54, 595 (1993). Review of pharmacology and clinical efficacy in herpes virus infections: C. M. Perry, D. Faulds, Drugs 52, 754-772 (1996). Clinical trial to prevent cytomegalovirus disease in renal transplantation: D. Lowance et al., N. Engl. J. Med. 340, 1462 (1999); to prevent transmission of genital herpes: L. Corey et al., ibid. 350, 11 (2004).
Derivative Type: Hydrochloride
CAS Registry Number: 124832-27-5
Manufacturers’ Codes: 256U; BW-256U87; BW-256
Trademarks: Valtrex (GSK)
Properties: Crystalline solid, occurs as hydrate. uv max (water): 252.8 nm (e 8530). Soly in water: 174 mg/ml.
Absorption maximum: uv max (water): 252.8 nm (e 8530)
Therap-Cat: Antiviral.
Keywords: Antiviral; Purines/Pyrimidinones
Valaciclovir is the hydrochloride salt of L-valyl ester of the antiviral drug aciclovir (Zovirax[R]). It was first launched in 1995 by GlaxoSmithKline (GSK) for the oral treatment of recurrent genital herpes, varicella zoster virus (VZV) and herpes simplex virus (HSV) infection in immunocompetent adults.
Valaciclovir was originally developed by GSK and was subsequently licensed to Sigma-Tau and Sanofi (formerly known as sanofi-aventis). In March 2003, GSK and Shionogi signed a letter of intent to copromote both aciclovir and valaciclovir in Japan, where it has been marketed by GSK since 2000.

Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster(shingles).[1] It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases.[1] It is taken by mouth.[1]

Common side effects include headache and vomiting.[1] Severe side effects may include kidney problems.[1] Use in pregnancy appears to be safe.[1] It is a prodrug, which works after being converted to aciclovir in a person’s body.[1]

Valaciclovir was patented in 1987 and came into medical use in 1995.[2][3] It is available as a generic medication.[4] A month supply in the United Kingdom costs the NHS about £3 as of 2019.[4] In the United States the wholesale cost of this amount is about US$2.80.[5]In 2016 it was the 168th most prescribed medication in the United States with more than 3 million prescriptions.[6]

Medical uses

Valtrex brand valaciclovir 500mg tablets

Valaciclovir is used for the treatment of HSV and VZV infections, including:[7]

  • Oral and genital herpes simplex (treatment and prevention)
  • Reduction of HSV transmission from people with recurrent infection to uninfected individuals
  • Herpes zoster (shingles): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days.[8]
  • Prevention of cytomegalovirus following organ transplantation
  • Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)[9]
  • Chickenpox in children ages 2-18)[10]

It has shown promise as a treatment for infectious mononucleosis[11][12][13] and is preventively administered in suspected cases of herpes B virus exposure.[14]

Valaciclovir is not recommended in Bell’s palsy due to lack of benefit.[15]

Adverse effects

Common adverse drug reactions (≥1% of people) associated with valaciclovir are the same as for aciclovir, its active metabolite. They include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, edemaarthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenialeukopenia, tremor, ataxiaencephalopathy, psychotic symptoms, crystalluriaanorexia, fatigue, hepatitisStevens–Johnson syndrometoxic epidermal necrolysis and/or anaphylaxis.[7]


Valaciclovir belongs to a family of molecules. Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir.[10] It is converted by esterases to the active drug, aciclovir, and the amino acidvaline, via hepatic first-pass metabolismAciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into a disphosphate by cellular guanylate kinase and then into the active triphosphate form, aciclo-GTP, by cellular kinases.[10]

Mechanism of action

Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of viral DNA replication. Aciclo-GTP competitively inhibits and inactivates the viral DNA polymerase.[10] Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolized within the cell, possibly by cellular phosphatases.[16]

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:[17]

The drug is predominantly active against HSV and, to a lesser extent, VZV. It is only of limited efficacy against EBV and CMV. However, valacyclovir has recently been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms.[11][12][13] Although it can prevent the establishment of viral latency, acyclovir therapy has not proven effective at eradicating latent viruses in nerve ganglia.[17]

As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity.[18]

It also is used for herpes B virus postexposure prophylaxis.[14]


Valaciclovir was patented in 1987 and came into medical use in 1995.[2][3] It is available as a generic medication.[4] A month supply in the United Kingdom costs the NHS about £3 as of 2019.[4] In the United States the wholesale cost of this amount is about US$2.80.[5] In 2019, it was the 168th most prescribed medication in the United States with more than 3 million prescriptions.[6]


It is marketed by GlaxoSmithKline under the trade names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 25, 2009.[19]

Valtrex is offered in 500 mg and 1 gram tablets, with the active ingredient valacyclovir hydrochloride. The inactive ingredients include carnauba wax, colloidal silicon dioxide, crospovidoneFD&C Blue No. 2 Lakehypromellosemagnesium stearatemicrocrystalline cellulosepolyethylene glycolpolysorbate 80povidone, and titanium dioxide.[20]


Acyclovir (I) was coupled with N-Cbz-L-valine (II) in the presence of DCC and DMAP to afford the Cbz-protected valyl ester (III). The N-benzyloxycarbonyl group of (III) was then removed by either hydrogenation over Pd/C or by transfer hydrogenation in the presence of formic acid. AU 8820978; EP 0308065; EP 0596542; JP 1989068373; JP 1991115284; US 4957924; US 5061708


In an alternative procedure, condensation of L-valine (IV) with methyl acetoacetate (V) in the presence of NaOH produced the enamine-protected valine sodium salt (VI). Condensation of (VI) with the tosylate (VII), (prepared from acyclovir (I) and tosyl chloride) afforded ester (VIII). Then, acidic hydrolysis of the enaminoester moiety of (VIII) furnished the target valine ester. Similar procedures were also reported using omega-mesyl and omega-chloro acyclovir.


The esterification of acyclovir (I) with N-(tert-butoxycarbonyl)-L-valine (II) by means of EDC, TEA and DMAP in DMF gives the corresponding ester (III) which is finally deprotected by means of HCl in water to afford the target valacyclovir.


    • Synonyms:Valacyclovir, BW-256U, 256 U 87
    • ATC:J05AB11
  • Use:antiviral, prodrug of aciclovir
  • Chemical name:l-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
  • Formula:C13H20N6O4
  • MW:324.34 g/mol
  • CAS-RN:124832-26-4
  • InChI:InChI=1S/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1



  • Formula:C13H20N6O4 • HCl
  • MW:360.80 g/mol
  • CAS-RN:124832-27-5

Substance Classes

Synthesis Path


    • US 4 957 924 (Burroughs Wellcome; 18.9.1990; GB-prior. 15.8.1987).
    • EP 308 065 (Wellcome Found. Ltd; appl. 12.8.1988; GB-prior. 15.8.1987, 5.11.1987).
  • combination with lamotrigine:

    • WO 9 505 179 (Wellcome Found. Ltd; appl. 17.8.1994; GB-prior. 18.8.1993).
  • water-dispersible tablets:

    • WO 9 213 527 (Wellcome Found. Ltd; appl. 29.1.1992; GB-prior. 30.1.1991, 22.11.1991, 25.11.1991).
  • medical use for preventing post herpetic neuralgia:

    • GB 2 282 759 (SmithKline Beecham; appl. 14.10.1994; GB-prior. 16.10.1993).


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  2. Jump up to:a b Long, Sarah S.; Pickering, Larry K.; Prober, Charles G. (2012). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN 1437727026.
  3. Jump up to:a b Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 504. ISBN 9783527607495.
  4. Jump up to:a b c d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 625–626. ISBN 9780857113382.
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  7. Jump up to:a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  8. ^ Lille, H. Martina; Wassilew, Sawko W. (2006). “Antiviral therapies of shingles in dermatology”. In Gross, Gerd; Doerr, H.W. (eds.). Herpes zoroster: recent aspects of diagnosis and control. Monographs in virology. 26. Basel (Switzerland): Karger Publishers. p. 124. ISBN 978-3-8055-7982-7. Retrieved January 1, 2012.
  9. ^ Elad S, Zadik Y, Hewson I, et al. (August 2010). “A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea”. Support Care Cancer18 (8): 993–1006. doi:10.1007/s00520-010-0900-3PMID 20544224.
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  12. Jump up to:a b Simon, Michael W.; Robert G. Deeter; Britt Shahan (March 2003). “The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study” (PDF)International Pediatrics18 (3): 164–169.[dead link]
  13. Jump up to:a b Balfour HH, Hokanson KM, Schacherer RM, et al. (May 2007). “A virologic pilot study of valacyclovir in infectious mononucleosis”. Journal of Clinical Virology39 (1): 16–21. doi:10.1016/j.jcv.2007.02.002PMID 17369082.
  14. Jump up to:a b “B Virus—First Aid and Treatment—Herpes B—CDC”. Retrieved June 6, 2015.
  15. ^ Baugh, Reginald F.; Basura, Gregory J.; Ishii, Lisa E.; Schwartz, Seth R.; Drumheller, Caitlin Murray; Burkholder, Rebecca; Deckard, Nathan A.; Dawson, Cindy; Driscoll, Colin (November 2013). “Clinical Practice Guideline: Bell’s Palsy”Otolaryngology–Head and Neck Surgery149 (3_suppl): S1–S27. doi:10.1177/0194599813505967ISSN 0194-5998In summary, antiviral therapy alone (acyclovir or valacyclovir) is not recommended in the treatment of Bell’s palsy due to lack of effectiveness of currently available drugs, unnecessary cost, and the potential for drug-related complications.
  16. ^[permanent dead link]
  17. Jump up to:a b O’Brien JJ, Campoli-Richards DM (March 1989). “Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy”. Drugs37 (3): 233–309. doi:10.2165/00003495-198937030-00002PMID 2653790.
  18. ^ Sweetman, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4OCLC 56903116.[page needed]
  19. ^ Ahmed, Rumman (November 27, 2009). “Ranbaxy Launches Generic Valtrex in U.S.”The Wall Street Journal. Retrieved January 16, 2010.
  20. ^ “Valtrex Prescribing Information” (PDF)GlaxoSmithKline. September 2008. Retrieved May 7, 2009.

External links

Valaciclovir structure.svg
Clinical data
Trade names Valtrex, Zelitrex, others
AHFS/ Monograph
MedlinePlus a695010
License data
  • AU: B3
  • US: B (No risk in non-human studies)
Routes of
By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 55%
Protein binding 13–18%
Metabolism Liver (to aciclovir)
Elimination half-life <30 minutes (valaciclovir);
2.5–3.6 hours (aciclovir)
Excretion Kidney 40–50% (aciclovir),
faecal 47% (aciclovir)
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.114.479 Edit this at Wikidata
Chemical and physical data
Formula C13H20N6O4
Molar mass 324.336 g/mol g·mol−1
3D model (JSmol)

//////////////Valacyclovir HCl,hydrochloride salt of L-valyl ester,  aciclovir, GlaxoSmithKline ,

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