Rule 2, omit O, gives C5H10
5 – 10/2 + 1 = 1 degree of unsaturation.
Look for 1 pi bond or aliphatic ring.
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A COX-2 inhibitor.
Mol wt: 356.439
CS-701; TG01, R-109339, TG-01 ,TP-1001
TP-2001, Capoxigem, Kymena, UNII-5X5HB3VZ3Z,
Daiichi Sankyo (innovator)Daiichi Sankyo Co Ltd,
Current developer: Tragara Pharmaceuticals, Inc.
Apricoxib is an orally bioavailable nonsteroidal anti-inflammatory agent (NSAID) with potential antiangiogenic and antineoplastic activities. Apricoxib binds to and inhibits the enzyme cyclooxygenase-2 (COX-2), thereby inhibiting the conversion of arachidonic acid into prostaglandins. Apricoxib-mediated inhibition of COX-2 may induce tumor cell apoptosis and inhibit tumor cell proliferation and tumor angiogenesis. COX-related metabolic pathways may represent crucial regulators of cellular proliferation and angiogenesis.
R-109339 is a cyclooxygenase-2 (COX-2) inhibitor currently in phase II clinical development at Tragara Pharmaceuticals for the oral treatment of non-small cell lung cancer (NSCLC) and for the treatment of inflammation. Additional phase II clinical trials are ongoing in combination with gemcitabine and erlotinib for the treatment of pancreas cancer. The company had been evaluating R-109339 for the treatment of colorectal cancer, but development for this indication was discontinued for undisclosed reasons. Daiichi Sankyo and Tragara Pharmaceuticals had been conducting phase II clinical trials with the drug candidate for the oral treatment of arthritis and for the treatment of breast cancer, respectively; however, no recent development for this indication has been reported.
COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid, which is derived from the cellular phospholipid bilayer by phospholipase A2. In addition to several other functions, prostaglandins act as messenger molecules in the process of inflammation. The compound is also designed to act against a well-defined cancer pathway that affects several routes of cancer pathogenesis. In preclinical cancer models, R-109339 demonstrated superiority to compounds with similar mechanisms of action and potential for use in combination with cisplatin. Furthermore, the compound demonstrated the ability to inhibit the cachexia and weight loss seen in mouse tumor models.
Apricoxib, (CS-706, 1) 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, a small-molecule, orally active, selective COX-2 inhibitor was discovered by investigators at Daiichi Sankyo in 1996. Clinical studies demonstrated potent analgesic activity and preclinical studies demonstrated good pharmacokinetics, pharmacodynamics and gastrointestinal tolerability. As an anticancer agent, preclinical studies demonstrated efficacy in biliary tract cancer models and colorectal carcinoma, and Recamp et al.
The original synthetic route is outlined below. Though the initial two steps were accomplished with decent yields, the final step of pyrrolidine formation followed by dehydration and dehydrocyanation produced only 3% of 1 as a brown powder. The yield in the last step of the synthesis of the 2-(4-methoxyphenyl) analog, 2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, was 6%, indicating that this synthesis route is problematic.
14 Kimura T, Noguchi Y, Nakao A, Suzuki K, Ushiyama S, Kawara A, Miyamoto M. 799823. EP. 1997:A1.
Published online Aug 19, 2011. doi: 10.1016/j.bmcl.2011.08.050
An efficient synthesis of apricoxib (CS-706), a selective cyclooxygenase inhibitor, was developed using copper catalysed homoallylic ketone formation from methyl 4-ethoxybenzoate followed by ozonolysis to an aldehyde, and condensation with sulphanilamide. This method provided multi-gram access of aprocoxib in good yield. Apricoxib exhibited potency equal to celecoxib at inhibition of prostaglandin E2 synthesis in two inflammatory breast cancer cell lines.
We envisioned that 7 could be prepared by ozonolysis of homoallylic ketone (8) (Route B). A recent development in the synthesis of homoallylic ketones by Dorr et al. via copper-catalyzed cascade addition of alkenylmagnesium bromide to an ester a24 was examined. Treatment of commercially available methyl 4-ethoxybenzoate with 1-propenylmagnesium bromide (4.0 equiv) in presence of CuCN (0.6 equiv) resulted in 95% yield of desired ketone8 after silica gel chromatography, along with a minor amount of unreacted ester).b25
The product was a mixture of cis/trans R/S stereoisomers, as detected in the 1H NMR spectrum, and was used directly in the next step without separation. Ozone was bubbled through a solution of 8 in MeOH/CH2Cl2 at −78°C, until all starting materials were consumed. The ozonide was then reduced to aldehyde 7 by treatment with Me2S overnight. Removal of volatiles and subsequent addition and evaporation of toluene gave the crude 1,4-dicarbonyl compound 7 which was sufficiently pure for the following condensation step. The 1H NMR signal at 9.78 ppm of the crude product confirmed the formation of the aldehyde. No attempt was made to characterize the enantiomeric ratio of 7 since the dehydration/aromatization reaction of the next step removes the chirality of the product. Treatment of 7 with sulfanilamide in 40% acetic acid-acetonitrile at 70°C for three hours resulted in a brown product. Purification by silica gel flash chromatography yielded 71% of pure 1 as a white solid.c26
1H, 13C, and COSY NMR spectra of compounds 1 and 8.
In one strategy, bromination of 4-ethoxyacetophenone (I) with Br2 yields 2-bromo-1-(4-ethoxyphenyl)ethanone (II) along with the byproduct 2-bromo-1-(3-bromo-4-ethoxyphenyl)ethanone, which are separated using HPLC. Alkylation of propionaldehyde N,Ndiisobutylenamine (III) with bromo ketone (II) and subsequent ketalization with neopentyl glycol (IV) using p-TsOH·H2O and, optionally, H2SO4 in MeCN gives monoprotected ketoaldehyde (V) (1). Finally, cyclization of ketoaldehyde derivative (V) with 4-aminobenzenesulfonamide (VI) in the presence of AcOH in PrOH/H2O at 90-100 °C furnishes apricoxib
Intermediate (V) can also be prepared by reaction of 1-(4- ethoxyphenyl)-2-buten-1-one (VII) with CH3NO2 in the presence of DBU in THF to produce nitro ketone (VIII). Subsequent treatment of nitroderivative (VIII) with neopentyl glycol (IV) and NaOMe and MeOH gives acetal (V) (2).In an alternativestrategy, condensation of 4-ethoxyacetaldehyde (IX) with 4-sulfamoylaniline (VI) in refluxing EtOH furnishesN-(4-ethoxybenzylidene)-
4-sulfamoylaniline (X), which then condenses with trimethylsilyl cyanide (XI) in the presence of ZnCl2 in THF yielding α- amino nitrile (XII). Cyclization of this compound with methacrolein (XIII) using LiHMDS in THF affords apricoxib
reference for above
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Method of using COX-2 inhibitors in the treatment and prevention of ocular COX-2 mediated disorders
1,2-diphenylpyrrole derivatives, their preparation and their therapeutic uses
Use of MEK inhibitors in treating abnormal cell growth
Therapeutic combinations comprising poly (ADP-ribose) polymerases inhibitor
Method for treating abnormal cell growth
Method of using a cyclooxygenase-2 inhibitor and sex steroids as a combination therapy for the treatment and prevention of dismenorrhea
Methods and compositions for treatment and prevention of tumors, tumor-related disorders and cachexia
Compositions of cyclooxygenase-2 selective inhibitors and NMDA receptor antagonists for the treatment or prevention of neuropathic pain
Methods for treating estrogen-dependent disorders
Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia
Method of using cox-2 inhibitors in the treatment and prevention of ocular cox-2 mediated disorders
Method of using a COX-2 inhibitor and an aromatase inhibitor as a combination therapy
Methods and Compositions for the Treatment of Cancer, Tumors, and Tumor-Related Disorders
HUMAN MONOCLONAL ANTIBODIES TO ACTIVIN RECEPTOR-LIKE KINASE-1
Use of cyclooxygenase-2 inhibitors for the treatment and prevention of tumours, tumour-related disorders and cachexia
Methods and compositions for the treatment and prevention of tumors, tumor-related disorders and cachexia
HETEROAROMATIC DERIVATIVES USEFUL AS ANTICANCER AGENTS
Human monoclonal antibodies to activin receptor-like kinase-1
BICYCLIC HETEROAROMATIC DERIVATIVES USEFUL AS ANTICANCER AGENTS
Pharmaceutical Compositions Comprising an Amorphous Form of a Vegf-R-Inhibitor
Compositions for the Treatment of Inflammation and Pain Using a Combination of a Cox-2 Selective Inhibitor and a Ltb4 Receptor Antagonist
1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses
Golden Root (Rhodiola rosea) – Also called Arctic Root or Roseroot, golden root is considered a queen of adaptogenic herbs. As one blogger puts it, “[Golden root] allows us to regulate our immune, physiological and neurological responses to stress, allowing us to survive not only rough environmental/weather challenges, but also to adapt and adjust our often neurotic mental habits and crazy social/political climates as well.
”The Russians use it to improve physical stamina and adapt to environmental stress. In Siberia, people still say, “Those who drink Rhodiola tea will live more than 100 years old.” The extract possesses positive mood enhancing and anti-stress properties with no detectable levels of toxicity. Golden root works by enhancing the body’s ability to make serotonin, dopamine, and other neurotransmitters that aid in happiness and stress-reduction.
Rhodiola rosea (commonly golden root, rose root, roseroot, Aaron’s rod, arctic root, king’s crown, lignum rhodium, orpin rose) is a perennial flowering plant in the family Crassulaceae. It grows in cold regions of the world, including much of the Arctic, the mountains ofCentral Asia, scattered in eastern North America from Baffin Island to the mountains of North Carolina, and mountainous parts of Europe, such as the Alps, Pyrenees, and Carpathian Mountains, Scandinavia, Iceland, Great Britain and Ireland. It grows on sea cliffs and on mountains at altitudes up to 2280 meters.[where?] Several shoots grow from the same thick root. Shoots may reach 5 to 35 cm in height. R. rosea is dioecious – having separate female and male plants.
Some studies have found support for it having antidepressant effects. It is not approved by the U.S. Food and Drug Administration (FDA) to cure, treat, or prevent any disease. In fact, the FDA has forcibly removed some products containing R. rosea from the market due to disputed claims that it treats cancer, anxiety, influenza, the common cold, bacterial infections, and migraines.
In Russia and Scandinavia, R. rosea has been used for centuries to cope with the cold Siberianclimate and stressful life. Such effects were provided with evidence in laboratory models of stress using the nematode C. elegans, and in rats in which Rhodiola effectively prevented stress-induced changes in appetite, physical activity, weight gain and the estrus cycle.
The aerial portion is consumed as food in some parts of the world, sometimes added to salads.
Scientists have identified about 140 chemical compounds in the subterranean portions of R. rosea. Rhodiola roots contain phenols,rosavin, rosin, rosarin, organic acids, terpenoids, phenolcarbonic acids and their derivatives, flavonoids, anthraquinones, and alkaloids.
The chemical composition of the essential oil from R. rosea root growing in different countries varies. For example, rosavin, rosarin and rosin at their highest concentration according to many tests can be found only in R. rosea of Russian origin; the main component of the essential oil from Rhodiola growing in Bulgaria are geraniol and myrtenol; in China the main components are geraniol and 1-octanol; and in India the main component is phenylethilic alcohol. Cinnamic alcohol was discovered only in the sample from Bulgaria.
R. rosea contains a variety of compounds that may contribute to its effects, including the class of rosavins that includes rosavin, rosarin, and rosin. Several studies have suggested that the most active components are likely to be rhodioloside and tyrosol, with other components being inactive when administered alone, but showing synergistic effects when a fixed combination of rhodioloside, rosavin, rosarin and rosin was used. Authentication, as well as potency, of R. rosea crude material and standardized extracts thereof are carried out with validated high-performance liquid chromatography analyses to verify the content of the marker constituents salidroside, rosarin, rosavin, rosin and rosiridin.
Although rosavin, rosarin, rosin and salidroside (and sometimes p-tyrosol, rhodioniside, rhodiolin and rosiridin) are among suspected active ingredients of R. rosea, these compounds are mostly polyphenols. There is no evidence that these chemicals have any physiological effect in humans that could prevent or reduce risk of disease.
Although these phytochemicals are typically mentioned as specific to Rhodiola extracts, there are many other constituent phenolic antioxidants, including proanthocyanidins,quercetin, gallic acid, chlorogenic acid and kaempferol.
Animal tests have suggested a variety of beneficial effects for R. rosea extracts, and there is some scientific evidence for its efficacy as a treatment for depression and fatigue  in humans.
R. rosea extract exerts an antifatigue effect that increases mental performance, particularly the ability to concentrate in healthy subjects and burnout patients with fatigue syndrome. Rhodiola significantly reduced symptoms of fatigue and improved attention after four weeks of repeated administration. A 2007 clinical trial from Armenia showed significant effect for a Rhodiola extract in doses of 340–680 mg per day in male and female patients from 18 to 70 years old with mild to moderate depression. No side effects were demonstrated at these doses. One study found inhibition of MAO-A and MAO-B. Studies on whether Rhodiola improves physical performance have been inconclusive, with some studies showing some benefit, while others show no significant difference.
Two systematic reviews on R. rosea extracts concluded that the research evidence is contradictory, and definite conclusions over its efficacy to relieve mental and physical fatigue are hampered by the lack of rigorously-designed, well-controlled randomized control trials 
R. rosea promotes the release of norepinephrine from rat pineal corpus cavernosum smooth muscle cell and artery endothelium cell, which was correlated with its effect of resisting senility. R. rosea extract has been found to increase the life span of fruit fly (Drosophila) by 24% independently of dietary restriction.
R. rosea may enhance the detoxification of many toxic heavy metals.
Gotu Kola (Centella asiatica) – An antiseptic, antispasmodic, peripheral vasodilator, and nerving and relaxant, this herb is known for calming depressive episodes, strengthening cognitive function, and helping one deal with both mental and physical stress.
Centella asiatica, commonly known as centella and gotu kola, is a small, herbaceous, annual plant of the family Mackinlayaceae or subfamily Mackinlayoideae of family Apiaceae, and is native to wetlands in Asia. It is used as a medicinal herb in Ayurvedic medicine,traditional African medicine, and traditional Chinese medicine. It is also known as the Asiatic pennywort or Indian pennywort in English, among various other names in other languages.
Centella grows in tropical swampy areas. The stems are slender, creeping stolons, green to reddish-green in color, connecting plants to each other. It has long-stalked, green, reniform leaves with rounded apices which have smooth texture with palmately netted veins. The leaves are borne on pericladial petioles, around 2 cm. The rootstock consists of rhizomes, growing vertically down. They are creamish in color and covered with root hairs.
The flowers are white or pinkish to red in color, born in small, rounded bunches (umbels) near the surface of the soil. Each flower is partly enclosed in two green bracts. The hermaphrodite flowers are minute in size (less than 3 mm), with 5-6 corolla lobes per flower. Each flower bears five stamens and two styles. The fruit are densely reticulate, distinguishing it from species of Hydrocotyle which have smooth, ribbed or warty fruit. The crop matures in three months, and the whole plant, including the roots, is harvested manually.
Centella grows along ditches and in low, wet areas. In Indian and Southeast Asian centella, the plant frequently suffers from high levels of bacterial contamination, possibly from having been harvested from sewage ditches. Because the plant is aquatic, it is especially sensitive to pollutants in the water, which are easily incorporated into the plant.
Centella is used as a leafy green in Sri Lankan cuisine, where it is called gotu kola. In Sinhalese, gotu is translated as “conical shape” andkola as “leaf”. It is most often prepared as malluma (මැල්ලුම), a traditional accompaniment to rice and curry, and goes especially well with vegetarian dishes, such as dhal, and jackfruit or pumpkin curry. It is considered quite nutritious. In addition to finely chopped gotu kola,malluma almost always contains grated coconut, and may also contain finely chopped green chilis, chili powder, turmeric powder and lime(or lemon) juice. A variation of the nutritious porridge known as kola kenda is also made with gotu kola by the Sinhalese people of Sri Lanka. Kola Kenda is made with very well-boiled red rice (with extra liquid), coconut milk and gotu kola, which is pureed. The porridge is accompanied with jaggery for sweetness. Centella leaves are also used in sweet “pennywort” drinks.
In Vietnam and Thailand, this leaf is used for preparing a drink or can be eaten in raw form in salads or cold rolls. In Bangkok, vendors in the famous Chatuchak Weekend Market sell it alongside coconut, roselle, chrysanthemum, orange and other health drinks.
It is one of the constituents of the Indian summer drink thandaayyee.
In Bangladeshi cuisine mashed centella is eaten with rice and is popular for its medicinal properties.
According to the American Cancer Society, although centella is promoted for its health benefits, “available scientific evidence does not support claims of its effectiveness for treating cancer or any other disease in humans”. However some research has shown a possible health benefit in the form of reduction of the progression of subclinical arterial lesions in low-risk asymptomatic subjects.
In South Asia, other common names of centella include సరస్వతి ఆకు (sarswathi aku) in Telugu; കുടവൻ (kudavan), മുത്തിൾ (muththil), or കുടങ്ങൽ (kudangal) in Malayalam; থানকুনি (thankuni) in Bengali; ගොටුකොල (gotu kola) in Sinhala; मधुकपर्णी (mandukaparni) inSanskrit; ब्राम्ही / ब्राह्मी (brahmi) in Marathi: ಒಂದೆಲಗ (ondelaga) in Kannada; வல்லாரை (vallaarai) in Tamil; brahmi booti in Hindi; perookin Manipuri; মানিমুনি (manimuni) in Assamese; timare in Tulu; tangkuanteh in Paite; ब्रह्मबुटि (brahmabuti) or घोड टाप्रे (ghod-tapre) in Nepali; and खोलचा घायँ (kholcha ghyan) in Newari (Nepal Bhasa).
In India, particularly, it is popularly known by a variety of names: bemgsag, brahma manduki, brahmanduki, brahmi, ondelaga or ekpanni (south India, west India), sarswathi aku(Andhra Pradesh), gotu kola, khulakhudi, mandukparni, mandookaparni, or thankuni (Bengal), depending on region. Bacopa monnieri is the more widely known Brahmi; both have some common therapeutic properties in Vedic texts and are used for improving memory. C. asiatica is called brahmi particularly in north India, although that may be a case of mistaken identity introduced during the 16th century, when brahmi was confused with mandukaparni, a name for C. asiatica.  Probably the earliest study ofmandookaparni as medya rasayana (improving the mental ability) was carried out at the Dr. A. Lakshmipathy Research Centre (now under CCRAS).
In Southeast Asia, it is known as ស្លឹកត្រចៀកក្រាញ់ (sleuk tracheakkranh) in Khmer; မြင်းခွာပင် (mying khwar ) in Burmese; ใบบัวบก (bai bua bok) in Thai; rau má (“mother vegetable”) in Vietnamese; pegagan or antanan in Indonesian; takip-kohol (literally “snail lid“) or yahong yahong (“little bowl”) in Filipino; and pegagan or pegaga in Malay.
Gotu kola is a minor feature in the longevity tradition of the T’ai chi ch’uan master Li Ching-Yuen. He purportedly lived to be 197 or 256, due in part to his usage of traditionalChinese herbs, including gotu kola.
Oat Straw (Avena sativa) – Not only can this herb effectively treat anxiety, it is also used to treat migraines, shingles, fatigue, and even epilepsy. This herb can be especially helpful in calming the nerves of those who are detoxing from drug or alcohol addiction, and can even help curb nicotine cravings.
Are you feeling stressed, tired, depressed, fed-up, run down or even lacking your usual sexual desire? If so, have you considered a daily dose of Avena sativa (also known as Oats or Oatstraw)?
This wonderful herb is thought to be soothing to the brain and nervous system, whilst at the same time increasing sexual desire, and performance, in both men and women!
Avena sativa is quickly becoming a popular natural alternative to pharmaceutical erection enhancers without the dangerous side effects. Also known as Oats Milky Seed or Oatstraw, Avena Sativa is used to stimulate both men and women quickly and effectively. It is often described as the “Natural Viagra”! Its stimulating effects are well known in the animal world, especially with horses where it is widely known that if you feed them oats their behaviour will be wild and energetic! And we’ve all heard the term “sowing your oats”.
Dr. Larry Clapp has studied alternative virility medicines extensively and concludes that “ten drops, under the tongue, twice a day works very powerfully to enhance erectile function.” Other studies have also suggested powerful results in both sexes.
In women, the effect seems to be that of increasing sexual desire rather than physical performance. Avena sativa contains compounds which are both sedative and soothing to the brain and nervous system, hence it is said to be a good herb as a nerve restorative. In women the aphrodisiac effect seems to work by relaxing the body which in turn allows a natural increase in desire.
In men it appears to be effective for treating impotence and premature ejaculation, probably by increasing healthy blood flow.
As a food, oats are known to be good for the heart because they keep blood fats under control. They also have other medicinal properties.
Avena sativa seeds are not only a rich source of carbohydrate and soluble fibre, they also have the highest content of Iron, Zinc and Manganese of any grain. It is said to be useful as a nerve restorative.
Avena sativa has no known side effects, unlike the sometimes dangerous sexual prescription drugs. It is used as a nervous system general tonic as well as a general health tonic.
Avena sativa is often the primary ingredient in expensive sexual formulas and in the popular alternatives Herbal V, Cobra and Biogra. There is no need to purchase expensive herbal formulas. The pure herb is more powerful and is not expensive to use.
Avena sativa does not appear to interact with drugs so it is often used as a safe alternative to other herbs that are used for anxiety, such as St John’s wort, which cannot be taken with many prescription medications. Avena sativa may also be of use in helping with drug withdrawal and is often combined with valerian and skullcap.
Oats are sometimes added to the bath as a topical treatment for the skin condition eczema. Generally, there are no side effects or contra-indications from using avena sativa herbal supplements.
Oatstraw is a cooling nervine and uterine tonic, anti-depressant, anti-spasmodic, nutritive, demulcent, and vulnerary herb. It’s high in vitamin E, protein, and minerals, and works by essentially feeding and soothing the nervous system, especially in times of stress, nervous exhaustion, and depression. It’s extremely helpful in menopause cases and with the recovery from shingles, estrogen deficiencies, persistant colds, and muscular sclerosis. As a tonic herb, it’s helpful for the whole system and can boost brain function and metabolism. It has high levels of silicic acid which help treat skin conditions such as excema, psoriasis, and irritations when applied externally as a soothing bath or compress. For depression, it combines well with lady’s slipper and skullcap. In Aryuvedic medicine, oatstraw is used for treating addictions and considered rejuvenating.
Oatstraw can be taken as a tincture, with 3-5 ml three times daily, made into an infusion to taste drunk throughout the day. An infusion of oatstraw is high in B vitamins and protein. Oats, the fruit of the plant, can be made into a porridge or gruel. For irritated skin, both oatstraw and oats can be used in a bath at 1 pound of straw to 2 liters of water, boiled for half an hour, added to the bath water. As a foot-soak, it can help rejuvenate tired feet, especially when combined with a little peppermint and green tea. Oats themselves can be ground up and used in skincare products like as washes and scrubs (such as in my Dirty Girl Facial Scrub) and added to bath waters.
Researchers see BPA effects in monkey mammary glands
Study adds to growing health concerns about common plastic additive
PULLMAN, Wash.—A new study finds that fetal exposure to the plastic additive bisphenol A, or BPA, alters mammary gland development in primates. The finding adds to the evidence that the chemical can be causing health problems in humans and bolsters concerns about it contributing to breast cancer.
“Previous studies in mice have demonstrated that low doses of BPA alter the developing mammary gland and that these subtle changes increase the risk of cancer in the adult,” says Patricia Hunt, a geneticist in Washington State University’s School of Molecular Biosciences. “Some have questioned the relevance of these findings in mice to humans. But finding the same thing in a primate model really hits uncomfortably close to home.”
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Radiotherapy for cancer involves exposing the patient or their tumor more directly to ionizing radiation, such as gamma rays or X-rays. The radiation damages the cancer cells irreparably. Unfortunately, such radiation is also harmful to healthy tissue, particularly the skin over the site of the tumor, which is then at risk of hair loss, dermatological problems and even skin cancer. As such finding ways to protect the overlying skin are keenly sought.
Writing in the International Journal of Low Radiation, Faruck Lukmanul Hakkim of the University of Nizwa, Oman and Nagasaki University, Nagasaki, Japan, and colleagues there and at Macquarie University, New South Wales, Australia, Bharathiar University, India and Konkuk University, South Korea, explain how three ubiquitous and well-studied natural products derived from plants can protect the skin against gamma radiation during radiotherapy.
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Sage Therapeutics (Originator)
For Epilepsy, status epilepticus
SGE-102; SAGE-547; allopregnanolone; allosteric GABA A receptor modulators (CNS disorders),
Sage Therapeutics receives fast track designation for status epilepticus therapy
Ligand Pharmaceuticals announced that its partner Sage Therapeutics has received fast track designation from the US Food and Drug Administration (FDA) for the Captisol-enabled SAGE-547 to treat status epilepticus.
|Chemical Name: (3α)-Allopregnanolone|
|Synonyms: (+)-3α-Hydroxy-5α-pregnan-20-one; (3α,5α)-3-Hydroxypregnan-20-one; 3α,5α-THP; 3α,5α-Tetrahydroprogesterone; 3α-Hydroxy-5α-dihydroprogesterone; 3α-Hydroxy-5α-pregnan-20-one; 3α-Hydroxy-5α-pregnane-20-one; 5α-Pregnan-3α-ol-20-one; 5α-Pregnane-3α-ol-20-one; Allopregnan-3α-ol-20-one; Allopregnanolone; Allotetrahydroprogesterone;|
|CAS Number: 516-54-1|
|Mol. Formula: C21H34O2|
|Appearance: White Solid|
|Melting Point: 174-176°C|
|Mol. Weight: 318.49|
In 2014, orphan drug designation was assigned in the U.S for the treatment of status epilepticus. In July 2014, fast track designation was received in the U.S. for the treatment of adults with super-refractory status epilepticus (SRSE).
SAGE Therapeutics, a biopharmaceutical company developing novel medicines to treat life-threatening, rare central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has granted fast track designation to the SAGE-547 development program. SAGE-547 is an allosteric modulator of GABAA receptors in development for the treatment of adult patients with refractory status epilepticus who have not responded to standard regimens (super-refractory status epilepticus, or SRSE). SAGE is currently evaluating SAGE-547 in a Phase 1/2 clinical trial for the treatment of SRSE. Preliminary data indicate that the first four patients enrolled in the clinical trial met the key efficacy endpoint, in that each was successfully weaned off his or her anesthetic agent while SAGE-547 was being administered. There have also been no reported drug-related serious adverse events in these four patients to date.
“The fast track designation for SAGE-547 recognizes the significant unmet need that exists in the treatment of super-refractory status epilepticus,” said Jeff Jonas, MD, chief executive officer of SAGE Therapeutics. “The receipt of orphan drug designation earlier this year for status epilepticus and the fast track designation are both significant regulatory milestones for SAGE-547, and we will continue to work closely with the FDA to advance our lead compound and the additional programs in our pipeline for the treatment of life-threatening CNS disorders.”
Fast track designation is granted by the FDA to facilitate the development and expedite the review of drug candidates that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.
SAGE-547 is an allosteric modulator of both synaptic and extra-synaptic GABAA receptors. GABAA receptors are widely regarded as validated drug targets for a variety of CNS disorders, with decades of research and multiple approved drugs targeting these receptor systems. SAGE-547 is an intravenous agent in Phase 1/2 clinical development as an adjunctive therapy, a therapy combined with current therapeutic approaches, for the treatment of SRSE.
About Status Epilepticus (SE)
SE is a life-threatening seizure condition that occurs in approximately 150,000 people each year in the U.S., of which 30,000 SE patients die.1 We estimate that there are 35,000 patients with SE in the U.S. that are hospitalized in the intensive care unit (ICU) each year. An SE patient is first treated with benzodiazepines, and if no response, is then treated with other, second-line, anti-seizure drugs. If the seizure persists after the second-line therapy, the patient is diagnosed as having refractory SE (RSE), admitted to the ICU and placed into a medically induced coma. Currently, there are no therapies that have been specifically approved for RSE; however, physicians typically use anesthetic agents to induce the coma and stop the seizure immediately. After a period of 24 hours, an attempt is made to wean the patient from the anesthetic agents to evaluate whether or not the seizure condition has resolved. Unfortunately, not all patients respond to weaning attempts, in which case the patient must be maintained in the medically induced coma. At this point, the patient is diagnosed as having SRSE. Currently, there are no therapies specifically approved for SRSE.
About SAGE Therapeutics
SAGE Therapeutics (NASDAQ: SAGE) is a biopharmaceutical company committed to developing and commercializing novel medicines to treat life-threatening, rare CNS disorders. SAGE’s lead program, SAGE-547, is in clinical development for super-refractory status epilepticus and is the first of several compounds the company is developing in its portfolio of potential seizure medicines. SAGE’s proprietary chemistry platform has generated multiple new compounds that target GABAA and NMDA receptors, which are broadly accepted as impacting many psychiatric and neurological disorders. SAGE Therapeutics is a public company launched in 2010 by an experienced team of R&D leaders, CNS experts and investors. For more information, please visitwww.sagerx.com.
|Jmol-3D images||Image 1|
|Molar mass||318.49 g/mol|
Allopregnanolone (3α-hydroxy-5α-pregnan-20-one or 3α,5α-tetrahydroprogesterone), generally abbreviated as ALLO or as 3α,5α-THP, is an endogenous inhibitory pregnane neurosteroid. It is synthesized from progesterone, and is a potent positive allosteric modulator of the GABAA receptor. Allopregnanolone has effects similar to those of other potentiators of the GABAA receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.
The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions.
The biosynthesis of allopregnanolone starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.
Depression, anxiety, and sexual dysfunction are frequently-seen side effects of 5α-reductase inhibitors such as finasteride, and are thought to be caused, in part, by interfering with the normal production of allopregnanolone.
Allopregnanolone acts as a potent positive allosteric modulator of the GABAA receptor. While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation. Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear. In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors, and also appears to act as a negative allosteric modulator of the 5-HT3 receptor. Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptors.
Unlike progesterone, allopregnanolone is inactive at the nuclear progesterone receptor (nPR). However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which is an agonist of the nPR, and thus/in accordance, allopregnanolone does appear to have indirect nPR-mediated progestogenic effects. In addition, allopregnanolone has recently been found to be an agonist of the newly-discovered membrane progesterone receptors (mPR), including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor. The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties. Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.
Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs), including α1 subtypes Cav1.2 and Cav1.3. However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain. Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone. Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5). However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.
Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding, prosocial, antiaggressive, prosexual, sedative, pro-sleep, cognitive and memory-impairing, analgesic, anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.
Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.
Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression. This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it. This seems to be a common effect of many GABAA receptor positive allosteric modulators. In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels), have been found to have negative effects on mood, while higher doses have a neutral effect.
Allopregnanolone and the other endogenous inhibitory neurosteroids have very short half-lives, and for this reason, have not been pursued for clinical use themselves. Instead, synthetic analogs with improved pharmacokinetic profiles, such as ganaxolone, have been synthesized and are being investigated. However, exogenous progesterone, such as oral micronized progesterone (OMP), reliably elevates allopregnanolone levels in the body with good dose-to-serum level correlations. Due to this, it has been suggested that OMP could be described as a prodrug of sorts for allopregnanolone. As a result, there has been some interest in using OMP to treat catamenial epilepsy, as well as other menstrual cycle-related and neurosteroid-associated conditions.
Materials and Methods
 The materials and methods used for the follwing experiments have been described in Griffin L.D., et al, Nature Medicine 10: 704-711 (2004). This reference is hereby incorporated by reference in its entirety.
Example 1: Allopregnanolone Treatment of Niemann Pick type-C Mice Substantially Reduces Accumulation of the Gangliosides GMl, GM2, and GM3 in the Brain  Mice were given a single injection of allopregnanolone, prepared in 20% βcyclodextrin in phosphate buffered saline, at a concentration of 25 mg/kg. The injection was on day 7 of life (P7, postnatal day 7). Concentrations of gangliosides GMl, GM2, GM3, were measured as well as other lipids such as ceramides and cerebrosides.
WO-2014031792 OR EQ
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FDA Approves Ryanodex for the Treatment of Malignant Hyperthermia
WOODCLIFF LAKE, N.J.(BUSINESS WIRE) July 23, 2014 —
Eagle Pharmaceuticals, Inc. (“Eagle” or “the Company”)
(Nasdaq:EGRX) today announced that the U. S. Food and Drug Administration (FDA)
has approved Ryanodex (dantrolene sodium) for injectable
suspension indicated for
the treatment of malignant hyperthermia (MH), along
with the appropriate supportive measures.
MH is an inherited and potentially fatal disorder triggered
by certain anesthesia agents
in genetically susceptible individuals. FDA had designated
Ryanodex as an Orphan Drug in
August 2013. Eagle has been informed by the FDA that it will learn over the next four to
six weeks if it has been granted the seven year Orphan Drug market exclusivity.
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Best practice paper on visual inspection to be published in September 2014
The ECA working group on visual inspection, which was founded this year, is going to publish its first document during the ECA event Particles in Parenterals and beyond. Read more.