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Nicox stock leaps on positive Ph III glaucoma drug data , 英文名称



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latanoprostene bunod, 英文名称

4- (nitrooxy) butyl (5Z) -7 – {(1R, 2R, 3R, 5S) -3,5-dihydroxy-2 – [(3R) -3-hydroxy-5-phenylpentyl] cyclopentyl} hept-5- enoate
CAS No.860005-21-6
Formula C 27 H 41 NO 8

2D chemical structure of 860005-21-6

SEPTEMBER 25, 2014
Shares in France’s Nicox have soared on positive late-stage data for its glaucoma drug Vesneo, partnered with Valeant’s Bausch + Lomb.

The firms have published top-line results from the pivotal Phase 3 studies conducted with Vesneo (latanoprostene bunod) for the reduction of intraocular pressure in patients with glaucoma or ocular hypertension. The drug is a nitric oxide-donating prostaglandin F2-alpha analog licensed by Nicox to Bausch + Lomb.

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prostaglandin nitrooxyderivatives, pharmaceutical compositions containing them and their use as drugs for treating glaucoma and ocular hypertension. Glaucoma is optic nerve damage, often associated with increased intraocular pressure (IOP), that leads to progressive, irreversible loss of vision. . Almost 3 million people in the United States and 14 million people worldwide have glaucoma; this is the third leading cause of blindness worldwide. Glaucoma occurs when an imbalance in production and drainage of fluid in the eye (aqueous humor) increases eye pressure to unhealthy levels. It is known that elevated IOP can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye or increase the fluid drainage, such as beta-blockers, α- agonists, ■ ‘ cholinergic agents, carbonic anhydrase inhibitors, or prostaglandin analogs. . Several side effects are associated with the drugs conventionally used to treat glaucoma. . ■ Topical beta-blockers show serious pulmonary side effects, depression, fatigue,’ confusion, impotence, hair loss, heart failure and bradycardia. Topical -agonists have a fairly high incidence of allergic, .or toxic reactions; topical cholinergic agents (miotics) can cause visual side effects. The side effects associated with oral carbonic anhydrase inhibitors include fatigue, anorexia, depression, paresthesias and serum■ electrolyte abnormalities (The Merck Manual of Diagnosis and Therapy, Seventeenth Edition, M. H. Beers and R. Berkow Editors, Sec. 8, Ch. 100) . Finally, the topical prostaglandin analogs (bimatoprost, latanoprost, travoprost and unoprostone) used in the treatment of glaucoma, can produce ocular side effects, such as increased pigmentation of the iris, ocular irritation, conjunctival hyperaemia, iritis, uveitis and macular oedema (Martindale, Thirty-third edition, p. 1.445) U.S. Pat. No. 3,922,293 describes monocarboxyacylates of prostaglandins F-type and their 15β isomers, at the C-9 position, and processes for preparing them; U.S. Pat. No. 6,417,228 discloses 13-aza prostaglandins having functional PGF receptor agonist activity and their use in treating glaucoma and ocular hypertension. WO 90/02553 discloses the use of prostaglandins derivatives of PGA, PGB, PGE and PGF, in which the omega chain contains a ring structure, for the treatment of glaucoma or ocular hypertension. WO 00/51978 describes novel nitrosated and/or nitrosylated prostaglandins, ‘ • in particular novel derivatives of PGEi, novel compositions and their use for treating sexual dysfunctions. • : U.S.- Pat. No. 5,625,083 discloses” ‘diriitroglycerol esters of prostaglandins which may be used as vasodilators, antihypertensive cardiovascular agents- or bronchodilators . U.S. Pat. No. 6,211,233 discloses compounds of the general formula A-Xι-N02, wherein A contains a ■■ – prostaglandin residue, .in ‘particular .PGEi, and Xi • is a bivalent connecting bridge; .’and their use fo ‘ treating impotence. It is an object of the present invention to provide new derivatives of prostaglandins able not only to eliminate or at least reduce the side ■ effects associated with these compounds, but also to possess an improved pharmacological activity. It has been surprisingly found that prostaglandin nitroderivatives have a significantly improved overall profile as compared to native, prostaglandins both in terms of -wider pharmacological .activity and enhanced tolerability. In particular, it has been recognized that the prostaglandin nitroderivatives of the present invention can be employed for treating glaucoma and ocular hypertension. The compounds of the present invention are indicated for the reduction of intraocular pressure in patients with open-angle glaucoma or with chronic angle- closure glaucoma who underwent peripheral iridotomy or laser iridoplasty.




Latanoprostene bunod

BOL303259 HDCurrently in Phase 3 clinical development with Nicox’s partner Bausch + Lomb

Latanoprostene bunod is a nitric oxide-donating prostaglandin F2-alpha analog in Phase 3 clinical development for the reduction of intraocular pressure in patients with glaucoma and ocular hypertension. It was licensed to Bausch + Lomb by Nicox in March 2010

Bausch + Lomb initiated a global Phase 3 program for latanoprostene bunod (previously known as BOL-303259-X and NCX 116) in January 2013. This pivotal Phase 3 program includes two separate randomized, multicentre, double-masked, parallel-group clinical studies, APOLLO andLUNAR, designed to compare the efficacy and safety of latanoprostene bunod administered once daily (QD) with timolol maleate 0.5% administered twice daily (BID) in lowering intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

The primary endpoint of both studies, which will include a combined total of approximately 800 patients, is the reduction in mean IOP measured at specified time points during three months of treatment. The Phase 3 studies are pivotal for U.S. registration and will be conducted in North America and Europe.

In July 2013, Bausch + Lomb initiated two additional studies in Japan: JUPITER (Phase 3) and KRONUS (Phase 1). A confirmatory efficacy study is expected to be required for the Japanese registration of latanoprostene bunod.

Phase 2b top-line results

A phase 2b study conducted by Bausch + Lomb with latanoprostene bunod met its primary efficacy endpoint and showed positive results on a number of secondary endpoints, including responder rate.
Bausch + Lomb conducted a randomized, investigator-masked phase 2b study to identify the most efficacious and safe dose of latanoprostene bunod for the reduction of IOP. The study enrolled 413 patients across 23 sites in the United States and Europe. Patients were randomized to receive either latanoprostene bunod (various concentrations) or latanoprost 0.005% once a day in the evening for 28 days.
The phase 2b study met its primary efficacy endpoint and showed positive results on a number of secondary endpoints. The primary efficacy endpoint was the reduction in mean diurnal IOP on day 28. Latanoprostene bunod consistently lowered IOP in a dose-dependent manner. All four doses tested showed greater IOP reduction compared with latanoprost 0.005%, with the differences for two of the four does reaching more than 1mmHg (statistical significance: p<0.01).
The most efficacious dose of latanoprostene bunod also showed positive results on a number of secondary endpoints, including consistently better control of IOP over 24 hours on day 28 as well as a statistically significant greater percentage of responders vs. latanoprost 0.005%, defined as patients achieving an IOP of 18mmHg or less. The responder rate was 68.7% for the most efficacious dose of latanoprostene bunod, compared to 47.5% for latanoprost 0.005% (p=0.006).
The safety of latanoprostene bunod was comparable to latanoprost. The most common adverse event was ocular hyperemia (red eye), which occurred at a similar rate across all treatment groups.

No new class of drugs has come to market for treating glaucoma since 1996, when the FDA approved the first prostaglandin analogue, latanoprost (Xalatan). That could change soon: Experts who follow drug development are hopeful that we’re on the brink of reaping the benefits of years of research.

“It’s been a decade and a half and counting since we’ve had new class of drugs to treat glaucoma. We’ve had formulary improvements and fixed combinations, but no novel agents,” said Louis B. Cantor, MD, at Indiana University. “We’ve gone through a long dry spell but are just beginning to see, in the last couple of years, exploration by pharma of some new types of drugs.” But, he added, “We don t know how well those will pan out.

The uncertainty about “panning out” involves both drug efficacy and marketplace issues. As Dr. Cantor said, “Prostaglandin analogues are pretty effective. For a company to go into the investment of developing a new class of drugs for glaucoma, they have to be better than prostaglandin analogues.

Andrew G. Iwach, MD, at the University of California, San Francisco, agreed: “This is a unique time period for glaucoma medications in that we have very good drugs, usually well tolerated. And they’ve gone generic. That’s important, because having such strong generic contenders out there makes it harder for drug companies to try to introduce new molecules into this arena. Specifically, the prostaglandin analogues have set a high bar. It’s hard to compete with them.

Given this barrier, what are the marketplace incentives for development? Sheer numbers, for a start: Ten thousand people a day turn 65, and this rate will continue for 18 years, Dr. Cantor said. “The number of people who are going to need treatment for glaucoma has already begun to increase substantially.

Even more important, “Despite all the advances, our medical therapy fails not only for compliance reasons, but just fails,” Dr. Cantor said. “We need to continue to have new alternatives for treatment that are more effective, that last longer, and that have simple dosing requirements.

Thus, any new drug that makes it from the bench to the clinic will be a welcome addition. “Obviously, we want new and better therapies. We still have no cure for glaucoma. And while half of all patients are treatable with one drug, half are not. So we still need additional therapies to treat glaucoma,” said Gary D. Novack, PhD, president of Pharmalogic Development.


EXAMPLE 1 Synthesis of [1R- [l (Z) , 2α (R*) , 3α, 5α] ] -7- [3, 5-dihydroxy-2- (3-hydroxy-5-phenylpentyl) cyclopentyl] -5-heptenoic acid 4- (nitrooxy) butyl ester (compound 1)

I Synthetic Pathway ONO,

MW 72.11 MW 153.02 MW 198.02

MW 390.51 MW 507.62

II EXPERIMENTAL II.1 Preparation of 4-bromobutanol

Tetrahydrofuran (12.5 g – 173 mmol) was charged under nitrogen in a reactor cooled to 5-10 °C. Hydrogen bromide (7.0 g. – 86.5 mmol) was then added slowly and the reaction ■medium was stirred over a period of 4.5 hours at 5-10°C. The mixture was diluted with 22.5 g of cold water and the pH of this solution was adjusted to pH=5-7 by adding 27.65% sodium hydroxide (2.0 g) keeping the temperature at 5-10 °C. The solution was then extracted twice with dichloromethane (13.25 g) . The combined organic phases were washed with -25% brine (7.5 g) , adjusted to pH=6-7 with 27.65% sodium hydroxide and dried over magnesium sulfate. Dichloromethane was distilled off and crude 4-bromobutanol (10.3 g – 66.9 mmol) was obtained in a yield of about 77%. II.2 Preparation of 4-bromobutyl nitrate

In reactor cooled to -5 to 5°C, nitric acid fuming (8.5 g – 135 mmol) was slowly added to a solution of 98% sulfuric acid (13.0 g – 130 mmol) in dichloromethane (18.0 g – 212 mmol). 4-bromobutanol (10.2 g – 66.6 mmol) was then added to this mixture and the reaction medium was stirred at -5 to 5°C over a period of 2-5 hours. The mixture was poured into cold water (110 g) keeping the temperature between -5 °C and 3°C. After decantation, the upper aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, adjusted to pH=6-7 by addition of 27.65% sodium hydroxide, washed with brine and dried over magnesium sulfate. Dichloromethane was distilled off under vacuum and crude 4-bromobutyl nitrate (12.7 g – 64.1 mmol) was recovered in a yield of about 96%.

II.3 Preparation of [1R- [lα-(Z) , 2β (R*) , 3α, 5α] ] -7- [3, 5- dihydroxy-2- (3-hydroxy-5-phenylpentyl) cyclopentyl] -5- heptenoic acid 4- (nitrooxy) butyl ester

Latanoprost acid (97.7%, S-isomer <1%) (213mg, 0.54 mmol) was dis.solved in 5.0 g anhydrous DMF. K2C03 (206′ mg, 1.49 mmol), KI (77 mg, 0.46 mmol) and 4-bromobutylnitrate (805 mg, .25% w/w in methylene chloride, 1.02 mmol) were added. The reaction mixture was heated and stirred on a rotary evaporator at 45-50°C. fter 1.5. hour, TLC (Si, CH2Cl2-MeOH, 5%) showed -no – starting acid. . . .. The reaction mixture was diluted with 100 ml ethyl acetate, washed with brine (3 x 50 ml), dried over MgS04 and evaporated to give yellowish oil (420 mg) .

5 1H NMR/13C NMR showed target molecule as a major product together with some starting 4-bromobutylnitrate and DMF. HPLC showed no starting acid. Residual solvent, 4- bromobutylnitrate and target ester were the main peaks. Butylnitrate ester showed similar UV spectrum as0 latanoprost and relative retention time was as expected.

Instrument: Bruker 300 MHz Solvent : CDC13 -5 H-NMR (CDC13) δ: 7.29-7.19 (5H, m, Ar) ; 5.45 (IH, m. CH=CH) ; 5.38 (IH, m, CH=CH) ;. 4.48 (2H, t, CH2-ON02) ; 4.18 (IH, m, CH-OH); 4.10 (2H, t, C00CH2) ; 3.95 (IH, m, CH-OH); 3.68 (IH, m, CH-OH); 2.87-2.60 (2H, ) ; 2.35 (2H, t) ; 2.25 (2H,m) ; 2.13 (2H,m) ; 1.90-1.35 (16H, m) .0 13C-NMR (CDCI3) ppm: 173.94 (C=0) ; 142.14; 129.55 (C5); 129.50 (C6) ; 128.50; 125.93 78.80 (Cu) ; 74.50 (C9) ; 72.70 (C-0N02) ; 71.39 (Ci5) ; 63.57; 52.99 (C12) 51.99 (C8); 41.30 (C10) ; 39.16 (Ci6) ; 33.66; 32.21; 29.73; 27.04; 26.70;5 25.04; 24.91; 23.72; 15.37.


October 2013 Feature
Trabecular meshwork structure. The colors in this drawing delineate the layers of the TM.
October 2013 Feature
Hyperemia. A side effect that emerged in trials of ROCK inhibitors is hyperemia; researchers are exploring different strategies to reduce it.

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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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