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ORGANIC SPECTROSCOPY

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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 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 amcrasto@gmail.com, 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......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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Evinacumab


(Heavy chain)
EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA ISGDGGSTYY
ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL RNTIFGVVIP DAFDIWGQGT
MVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP
AVLQSSGLYS LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF
LGGPSVFLFP PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE
QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS
QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK
SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK ASSLESGVPS
RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H140-L214, H153-H209, H232-H’232, H235-H’235, H267-H327, H373-H431, H’22-H’96, H’140-L’214, H’153-H’209, H’267-H’327, H’373-H’431, L23-L88, L134-L194, L’23-L’88, L’134-L’194)

Evinacumab

エビナクマブ (遺伝子組換え)

Immunoglobulin G4, anti-​(human protein ANGPTL3 (angiopoietin-​like 3)​) (human monoclonal REGN1500 heavy chain)​, disulfide with human monoclonal REGN1500 light chain, dimer

FormulaC6480H9992N1716O2042S46
CAS1446419-85-7
Mol weight146081.9345

Protein Sequence

Sequence Length: 1334, 453, 453, 214, 214multichain; modified (modifications unspecified)

FDA APPROVED,  2021/2/11, EVKEEZA

Antihyperlipidemic, Anti-angiopietin like 3

Monoclonal antibody
Treatment of dyslipidemia

  • REGN 1500
  • REGN-1500
  • REGN1500

Sequence:

1EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA51ISGDGGSTYY ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL101RNTIFGVVIP DAFDIWGQGT MVTVSSASTK GPSVFPLAPC SRSTSESTAA151LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS201SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP251PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE301QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR351EPQVYTLPPS QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT401PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS451LGK

Sequence:

1EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA51ISGDGGSTYY ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL101RNTIFGVVIP DAFDIWGQGT MVTVSSASTK GPSVFPLAPC SRSTSESTAA151LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS201SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP251PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE301QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR351EPQVYTLPPS QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT401PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS451LGK

Sequence:

1DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK51ASSLESGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ101GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV151DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG201LSSPVTKSFN RGEC

Sequence:

1DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK51ASSLESGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ101GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV151DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG201LSSPVTKSFN RGEC

Sequence Modifications

TypeLocationDescription
bridgeCys-22 – Cys-96disulfide bridge
bridgeCys-140 – Cys-214”disulfide bridge
bridgeCys-153 – Cys-209disulfide bridge
bridgeCys-232 – Cys-232′disulfide bridge
bridgeCys-235 – Cys-235′disulfide bridge
bridgeCys-267 – Cys-327disulfide bridge
bridgeCys-373 – Cys-431disulfide bridge
bridgeCys-22′ – Cys-96′disulfide bridge
bridgeCys-140′ – Cys-214”’disulfide bridge
bridgeCys-153′ – Cys-209′disulfide bridge
bridgeCys-267′ – Cys-327′disulfide bridge
bridgeCys-373′ – Cys-431′disulfide bridge
bridgeCys-23” – Cys-88”disulfide bridge
bridgeCys-134” – Cys-194”disulfide bridge
bridgeCys-23”’ – Cys-88”’disulfide bridge
bridgeCys-134”’ – Cys-194”’disulfide bridge

PATENTS

WO 2017024062

 US 20170305999 

Evinacumab, sold under the brand name Evkeeza, is a monoclonal antibody medication for the treatment of homozygous familial hypercholesterolemia (HoFH).[1][2]

Evinacumab is a recombinant human IgG4 monoclonal antibody targeted against angiopoietin-like protein 3 (ANGPTL3) and the first drug of its kind. The ANGPTL family of proteins serve a number of physiologic functions – including involvement in the regulation of lipid metabolism – which have made them desirable therapeutic targets in recent years.2 Loss-of-function mutations in ANGPTL3 have been noted to result in hypolipidemia and subsequent reductions in cardiovascular risk, whereas increases in function appear to be associated with cardiovascular risk, and it was these observations that provided a rationale for the development of a therapy targeted against ANGPTL3.3

In February 2021, evinacumab became the first-and-only inhibitor of ANGPTL3 to receive FDA approval after it was granted approval for the adjunctive treatment of homozygous familial hypercholesterolemia (HoFH) under the brand name “Evkeeza”.8 Evinacumab is novel in its mechanism of action compared with other lipid-lowering therapies and therefore provides a unique and synergistic therapeutic option in the treatment of HoFH.

Common side effects include nasopharyngitis (cold), influenza-like illness, dizziness, rhinorrhea (runny nose), and nausea. Serious hypersensitivity (allergic) reactions have occurred in the Evkeeza clinical trials.[2]

Evinacumab binds to the angiopoietin-like protein 3 (ANGPTL3).[2] ANGPTL3 slows the function of certain enzymes that break down fats in the body.[2] Evinacumab blocks ANGPTL3, allowing faster break down of fats that lead to high cholesterol.[2] Evinacumab was approved for medical use in the United States in February 2021.[2][3]

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
EvkeezaInjection, solution, concentrate150 mg/1mLIntravenousRegeneron Pharmaceuticals, Inc.2021-02-11Not applicableUS flag 
EvkeezaInjection, solution, concentrate150 mg/1mLIntravenousRegeneron Pharmaceuticals, Inc.2021-02-11Not applicableUS flag 
EVKEEZA™ (evinacumab-dgnb) INJECTION | Regeneron Corporate

History

The effectiveness and safety of evinacumab were evaluated in a double-blind, randomized, placebo-controlled, 24-week trial enrolling 65 participants with homozygous familial hypercholesterolemia (HoFH).[2] In the trial, 43 participants received 15 mg/kg of evinacumab every four weeks and 22 participants received the placebo.[2] Participants were taking other lipid-lowering therapies as well.[2]

The primary measure of effectiveness was the percent change in low-density lipoprotein (LDL-C) from the beginning of treatment to week 24.[2] At week 24, participants receiving evinacumab had an average 47% decrease in LDL-C while participants on the placebo had an average 2% increase.[2]

The U.S. Food and Drug Administration (FDA) granted the application for evinacumab orphan drugbreakthrough therapy, and priority review designations.[2] The FDA granted approval of Evkeeza to Regeneron Pharmaceuticals, Inc.[2]

References

  1. Jump up to:a b https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761181s000lbl.pdf
  2. Jump up to:a b c d e f g h i j k l m n “FDA approves add-on therapy for patients with genetic form of severely”U.S. Food and Drug Administration (FDA). 11 February 2021. Retrieved 12 February 2021.  This article incorporates text from this source, which is in the public domain.
  3. ^ “FDA Approves First-in-class Evkeeza (evinacumab-dgnb) for Patients with Ultra-rare Inherited Form of High Cholesterol” (Press release). Regeneron Pharmaceuticals. 11 February 2021. Retrieved 12 February 2021 – via PR Newswire.

Further reading

External links

Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetAngiopoietin-like 3 (ANGPTL3)
Clinical data
Trade namesEvkeeza
Other namesREGN1500, evinacumab-dgnb
License dataUS DailyMedEvinacumab
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number1446419-85-7
DrugBankDB15354
ChemSpidernone
UNIIT8B2ORP1DW
KEGGD11753
Chemical and physical data
FormulaC6480H9992N1716O2042S46
Molar mass146083.95 g·mol−1

//////////////

#Evinacumab, #Peptide, #APPROVALS 2021, #FDA 2021, #Monoclonal antibody, #dyslipidemia, #エビナクマブ (遺伝子組換え) , #REGN 1500, #REGN-1500, #REGN1500, #Anthony melvin crasto, #world drug tracker. # new drug approvals, #pharma

Pemafibrate, Пемафибрат , بيرمافيبرات , 佩玛贝特 , ペマフィブラート ,


 

 

img

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)

UPDATE ADDED  ON MARCH 2017

Pemafibrate.svg

ChemSpider 2D Image | pemafibrate | C28H30N2O6

Pemafibrate

  • Molecular FormulaC28H30N2O6
  • Average mass490.548 Da
Пемафибрат [Russian] [INN]
بيرمافيبرات [Arabic] [INN]
佩玛贝特 [Chinese] [INN]
ペマフィブラート
(2R)-2-[3-[[1,3-benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butyric acid
(R)-2-(3-((benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy)butanoic acid
848259-27-8 [RN]
CHEMBL247951
K-13675, (R)-
UNII:17VGG92R23
(2R)-2-[3-({1,3-Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid
Butanoic acid, 2-[3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]-, (2R)-
Parmodia (TN)
Antihyperlipidemic, Triglyceride synthesis inhibitor, Peroxisome proliferator-activated receptor (PPAR) alpha agonist

Pemafibrate, marketed as Parmodia, is a peroxisome proliferator-activated receptor alpha (PPARα) agonist. It is developed and marketed by Kowa Pharmaceuticals.

In 3 July 2017, Pharmaceuticals and Medical Devices Agency approved it in Japan. It is available in 0.1 mg tablets.[1]

References

  1.  Pemafibrate, pharmacodia.com
ペマフィブラート
Pemafibrate

C28H30N2O6 : 490.55
[848259-27-8]
Pemafibrate
Pemafibrate.svg
Clinical data
Trade names Parmodia
Synonyms K-13675
Routes of
administration
Oral
Identifiers
CAS Number
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C28H30N2O6
Molar mass 490.56 g·mol−1
3D model (JSmol)

////////////Pemafibrate, Пемафибрат بيرمافيبرات 佩玛贝特 ,  ペマフィブラート , 

 

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
str6

Reference:1. US2009023944A1.

Route 2
str6

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
str6

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

 

Zydus-Cadila is developing ZYH-7, a PPAR alpha modulator for the potential treatment of dyslipidemia


ZYH-7
Prediction of ZYH 7 below……..If it does not match then ZYH 7 will be a very close structure
WP_000331
1014989-63-9
Acetic acid, 2-​[2-​methyl-​4-​[1-​[[[4-​methyl-​2-​[4-​(trifluoromethyl)​phenyl]​-​ 5-​thiazolyl]​methoxy]​imino]​ethyl]​phenoxy]​-

Zydus-Cadila is developing ZYH-7, a PPAR alpha modulator for the potential treatment of dyslipidemia .

By January 2012, phase II trials had begun ; in January 2014, the drug was still listed as being in phase II development

By January 2012 phase II trials had begun for Diabetes type 2 Lipoprotein disorders
Obesity

In August 2007, an IND was filed , and by March 2008, a phase I trial was underway ; by April 2011, the trial had been completed

Zydus Cadila has filed an Investigational New Drug (NID) application for seeking DCGI’s permission for conducting clinical trials for its New Molecular Entity (NME) ZYH7.
 
According to a company release, it claims that ZYH7 is a novel drug candidate for treating dyslipidemia and metabolic disorders. The company inform that ZYH7 had been conceptualised and developed by its scientists from Zydus Research Centre.
The company has its in-house research centre and it had recently concluded pre-clinical studies on ZYH7, which have reported interesting and encouraging finding which indicate a novel molecule to treat dyslipidemia and associated metabolic disorders.
Commenting on the new development, Pankaj Patel, chairman and managing director, Zydus Cadila said, “We have been building a promising pipeline of new molecular entities at the Zydus Research Centre and ZYH7 is an important step in this direction”.
Starting with its first IND filing in 2005, Zydus today has four INDs in various stages of clinical trials. NME – ZYH1 for treating dyslipidemia and ZYI1 for treating pain and inflammation are undergoing Phase II trials. ZYH2 for treating diabetes and the novel CB-1 antagonist, ZYO1 for treating obesity, are undergoing Phase I trials.
Diabetes, a worldwide health problem, affects more than 150 million people, a number expected to double to 300 million by 2025. People with diabetes are at especially high risk for dyslipidemia, particularly high triglyceride levels and low HDL levels.
Dyslipidemia is also a key independent risk factor for cardiovascular disease (CVD), which is the largest therapeutic segment in the world pharmaceutical market.
With an increasing correlation between several endocrine and metabolic disorders, there has been considerable emphasis in recent times on metabolic syndrome. The metabolic components of cardiovascular disease, diabetes and obesity, are linked in numerous ways with each having an impact on the other.
For instance, it is also well known that patients with Type 2 diabetes have a two to four-fold excess risk of coronary heart disease and that these patients very often have increased cardiovascular risk factors even before the onset of their diabetes.

Dyslipidemia is an abnormal amount of lipids (e.g. cholesterol and/or fat) in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin levels can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

Dyslipidemia
Classification and external resources
ICD10 E78
ICD9 272
DiseasesDB 33452
MeSH D050171

Classification

Physicians and basic researchers classify dyslipidemias in two distinct ways:

  • Phenotype, or the presentation in the body (including the specific type of lipid that is increased)
  • Etiology, or the reason for the condition (genetic, or secondary to another condition). This classification can be problematic, because most conditions involve the intersection of genetics and lifestyle issues. However, there are a few well-defined genetic conditions that are usually easy to identify.

Fredrickson Classification:[1]

For more a detailed version, see Hyperlipidemia#Classification.
Phenotype I IIa IIb III IV V
Elevated Lipoprotein Chylomicron LDL LDL and VLDL IDL VLDL VLDL and chylomicrons

WO 2008035359

https://www.google.com/patents/WO2008035359A2?cl=en

Scheme 1 below which comprises:

Scheme 2 below which comprises

Citing Patent Filing date Publication date Applicant Title
WO2009021740A2 Aug 14, 2008 Feb 19, 2009 Sanofis Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2010049946A2 * Oct 22, 2009 May 6, 2010 Cadila Healthcare Limited Thyroid receptor ligands
WO2010084512A1 * Dec 22, 2009 Jul 29, 2010 Cadila Healthcare Limited Novel oxime derivatives
WO2010110479A1 * Mar 24, 2010 Sep 30, 2010 Nippon Chemiphar Co., Ltd. Activator for peroxisome proliferator-activated receptor
WO2011157827A1 Jun 17, 2011 Dec 22, 2011 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2013037390A1 Sep 12, 2011 Mar 21, 2013 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2014192023A1 * May 20, 2014 Dec 4, 2014 Cadila Healthcare Limited Novel compounds suitable for the treatment of dyslipidemia
EP2567959A1 Sep 12, 2011 Mar 13, 2013 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
US8742117 Dec 22, 2009 Jun 3, 2014 Cadila Healthcare Limited Oxime derivatives
US8822414 * Dec 26, 2011 Sep 2, 2014 Cadila Healthcare Limited Heterocyclic compounds suitable for the treatment of dyslipidemia

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PARIS

Map of paris

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