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Pemafibrate

NDA Filing Japan, Phase 2 in EU, US

A PPAR-α agonist potentially for the treatment of dyslipidemia.

K-877, K-13675, (R)-

CAS No. 848259-27-8,

Molecular Formula,C28-H30-N2-O6,Molecular Weight,490.553

(2R)-2-[3-({(1,3-benzoxazol-2-yl)[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid
(R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butyric acid
  • Originator Kowa Pharmaceutical
  • Class Antihyperlipidaemics
  • Mechanism of Action Peroxisome proliferator-activated receptor alpha agonists
  • Preregistration Dyslipidaemias

Most Recent Events

  • 01 Feb 2016 Kowa Research Institute completes a phase I drug-interaction trial in Healthy volunteers in USA (PO) (NCT02719431)
  • 12 Jan 2016 Kowa Research Institute plans the phase III PROMINENT trial for Dyslipidaemia (In patients with diabetes mellitus) in countries worldwide
  • 01 Jan 2016 Kowa Research Institute initiates a phase I drug-interaction trial in Healthy volunteers in USA (PO) (NCT02719431)

Pemafibrate, also known as K-877 and (R)-K 13675, is a PPAR alpha agonist. (R)-K-13675 decreases the secretion of inflammatory markers without affecting cell proliferation or tube formation. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a key regulator of lipid and glucose metabolism and has been implicated in inflammation. (R)-K-13675 was associated with the inhibition of inflammatory responses without affecting cell proliferation or angiogenesis, and subsequently may induce an anti-atherosclerotic effect.

Pemafibrate had been filed NDA by Kowa for the treatment of dyslipidemia in the Japan in 2015.

Pemafibrate is in phase II clinical trials for the treatment of dyslipidemia in the US and EU.

 

 

Route 1
Reference:1. US2009023944A1.

Route 2
Reference:1. US2009076280A1.

http://www.google.com/patents/US20090076280

Example 5 Synthesis of (R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butyric acid (Compound (6))

  • Ethyl (R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butylate (26.0 g) was dissolved in ethanol (200 mL), and 1.5N NaOH (50 mL) was added to the solution, followed by stirring for 1 hour at room temperature. The reaction mixture was washed with diethyl ether, and the formed aqueous layer was acidified with 4N HCl under ice cooling. The thus-treated aqueous layer was extracted with ethyl acetate, and the extract was washed sequentially with water and saturated brine. The washed extract was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol=10/1), to thereby yield the target product (21.3 g, 87%, 98% ee).

Optical Purity:

  • Measurement conditions: HPLC
  • Column: CHIRALPAK AD
  • Solvent: n-hexane/IPA/TFA=100/30/0.1
  • Flow rate: 2 mL/min
  • Retention time: 4.19 min (S-form; 3.68 min)
  • 1H-NMR (400 MHz, CD3OD) δ ppm: 0.94 (t, J=7 Hz, 3H), 1.81 (m, 2H), 1.99 (quintet, J=6 Hz, 2H), 3.60 (t, J=7 Hz, 2H), 3.61 (s, 3H), 3.85 (t, J=6 Hz, 2H), 4.40 (t, J=6 Hz, 1H), 4.65 (s, 2H), 6.69-6.80 (m, 7H), 6.91 (dt, J=7, 1 Hz, 1H), 7.05 (dt, J=7, 1 Hz, 1H), 7.12-7.18 (m, 4H).

 

Route 3
Reference:1. Bioorg. Med. Chem. Lett. 200717, 4689-4693.

 

Landmark Trial Entitled “PROMINENT” To Explore The Prevention Of Heart Disease In Diabetic Patients With High Triglycerides And Low HDL-C

Trial will evaluate if lowering triglycerides and increasing functional HDL with Kowa’s potent selective peroxisome proliferator activator receptor-alpha (PPAR-alpha) modulator, K-877 (pemafibrate) can reduce the elevated risk of cardiovascular disease in high-risk diabetic patients who are already taking statins

Jan 12, 2016, 09:00 ET from Kowa Research Institute, Inc.

RESEARCH TRIANGLE PARK, N.C., Jan. 12, 2016 /PRNewswire/ — Kowa Research Institute, Inc., announced plans to conduct an international, multi-center cardiovascular outcomes trial evaluating triglyceride reduction and increasing functional HDL with K-877 (pemafibrate), in high-risk diabetic patients with high triglyceride and low HDL-C levels who are already taking statins.  K-877 is a highly potent and selective peroxisome proliferator activator receptor-alpha (PPAR-alpha) modulator (SPPARMalpha), a promising category of metabolic therapy.

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention (CCVDP) at Brigham and Women’s Hospital (BWH), a teaching affiliate of Harvard Medical School, and Aruna Pradhan, MD, a cardiologist at BWH, will be co-Principal Investigators of the planned trial.

“This trial is unprecedented,” said Gary Gordon, MD, President, Kowa Research Institute, Inc. “Statins are effective in lowering cardiovascular risk among patients with high cholesterol, but residual risk remains, particularly in patients with high triglyceride levels and low HDL-C levels.  Kowa will be the first company to run a major, randomized clinical trial investigating whether modulating PPAR-alpha to lower triglycerides and increase functional HDL in diabetic patients can reduce cardiovascular risk when added to statin therapy.”

Evidence supports a role for triglyceride-rich lipoproteins and low HDL-C as important contributors to atherosclerosis.  Kowa specifically set out to create the most potent and selective PPAR-alpha modulator ever developed, and succeeded with K-877, which is at least 1,000 times as potent and selective as other drugs.  Kowa has completed clinical development of K-877 for hyperlipidemia in Japan, and has submitted it to the PMDA for approval as a new drug.  Kowa’s clinical studies have shown K-877 significantly reduces triglycerides, ApoC3, and remnant cholesterol and increases functional HDL and FGF21.

The Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN diabetic patiENTs (PROMINENT) Phase 3 K-877 cardiovascular outcomes trial will recruit an estimated 10,000 high-risk diabetic patients worldwide.  All participants will receive aggressive, standard of care management of cardiovascular risk factors including treatment with high-intensity statins.  In addition, patients will receive either K-877 or placebo.  The trial will include diabetic patients with and without established cardiovascular disease and will test whether K-877 reduces the occurrence of heart attacks, hospitalizations for unstable angina requiring unplanned revascularization, stroke, or death from cardiovascular causes.

“Cardiovascular disease remains the number one cause of death worldwide,” said Dr. Gordon.  “Reducing residual cardiovascular risk with K-877 would be valuable to physicians managing patients’ cardiovascular disease.”

About Kowa Company, Ltd. and Kowa Research Institute, Inc.
Kowa Company, Ltd. (Kowa) is a privately held multinational company headquartered in Nagoya, Japan. Established in 1894, Kowa is actively engaged in various manufacturing and trading activities in the fields of pharmaceuticals, life science, information technology, textiles, machinery and various consumer products. Kowa’s pharmaceutical division is focused on research and development for cardiovascular therapeutics (dyslipidemia, type 2 diabetes and atherosclerosis), ophthalmology and anti-inflammatory agents. The company’s flagship product, LIVALO® (pitavastatin), is approved in 45 countries around the world.

Kowa Research Institute, Inc., headquartered in Research Triangle Park, NC, is the division of Kowa responsible for the clinical development of Kowa’s new drugs in the United States. Kowa Research Institute was established in 1997 in California and began operations at the current location in 2003.  For more information about Kowa Research Institute, visit www.kowaus.com.

1 NCT00610441 Dose Finding Study in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)(174007/P05805/MK-8777-003) Completed Drug: MK-8777|Drug: Placebo Phase 2 Merck Sharp & Dohme Corp.
2 NCT00610649 Trial to Determine the Maximum Tolerated Dose (MTD) Based on Safety and Tolerability, of Org 26576 in Participants With Major Depressive Disorder (174001/P05704/MK-8777-001) Completed Drug: MK-8777|Drug: Placebo Phase 2 Merck Sharp & Dohme Corp.
3 NCT02073084 A Thorough Corrected QT Interval Trial Completed Drug: K-877 Low Dose|Drug: Moxifloxacin|Other: Placebo|Drug: K-877 High Dose Phase 1 Kowa Research Institute, Inc.
4 NCT02273986 Drug-Drug Interaction Study in Health Adult Volunteers Completed Drug: Digoxin|Drug: K-877 Phase 1 Kowa Research Institute, Inc.
5 NCT02275962 Drug-Drug Interaction Study in Healthy Adult Volunteers Active, not recruiting Drug: K-877|Drug: Rifampin Phase 1 Kowa Research Institute, Inc.
6 NCT02275975 Drug-Drug Interaction Study in Healthy Adult Volunteers Completed Drug: K-877|Drug: Fluconazole Phase 1 Kowa Research Institute, Inc.
7 NCT02275988 Drug-Drug Interaction Study in Healthy Adult Volunteers Completed Drug: K-877|Drug: Clarithromycin Phase 1 Kowa Research Institute, Inc.
8 NCT02276001 Drug-Drug Interaction Study in Healthy Adult Volunteers Completed Drug: K-877|Drug: Cyclosporine Phase 1 Kowa Research Institute, Inc.

2D chemical structure of 848259-27-8

US6653334 * Dec 27, 2002 Nov 25, 2003 Kowa Co., Ltd. Benzoxazole compound and pharmaceutical composition containing the same
US7109226 * Sep 3, 2004 Sep 19, 2006 Kowa Co., Ltd. PPAR-activating compound and pharmaceutical composition comprising the compound
US7183295 * Apr 20, 2006 Feb 27, 2007 Kowa Co., Ltd. PPAR-activating compound and pharmaceutical composition comprising the compound

///////Pemafibrate, NDA,  Kowa, dyslipidemia,  Japan, 2015, phase II clinical trials,  US and EU, K-877, K-13675, (R)-

CC[C@H](C(=O)O)Oc1cccc(c1)CN(CCCOc2ccc(cc2)OC)c3nc4ccccc4o3

CC[C@@H](OC1=CC=CC(CN(C2=NC3=CC=CC=C3O2)CCCOC4=CC=C(OC)C=C4)=C1)C(O)=O

 


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , 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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