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CILOFEXOR

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Cilofexor.png

Cilofexor Chemical Structure

 

 

CILOFEXOR

C28H22Cl3N3O5 ,

586.8 g/mol

1418274-28-8

GS-9674, Cilofexor (GS(c)\9674)

UNII-YUN2306954

YUN2306954

2-[3-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]phenyl]-3-hydroxyazetidin-1-yl]pyridine-4-carboxylic acid

Cilofexor is under investigation in clinical trial NCT02943447 (Safety, Tolerability, and Efficacy of Cilofexor in Adults With Primary Biliary Cholangitis Without Cirrhosis).

Cilofexor (GS-9674) is a potent, selective and orally active nonsteroidal FXR agonist with an EC50 of 43 nM. Cilofexor has anti-inflammatory and antifibrotic effects. Cilofexor has the potential for primary sclerosing cholangitis (PSC) and nonalcoholic steatohepatitis (NASH) research.

Gilead , following a drug acquisition from  Phenex , is developing cilofexor tromethamine (formerly GS-9674), the lead from a program of farnesoid X receptor (FXR; bile acid receptor) agonists, for the potential oral treatment of non-alcoholic steatohepatitis (NASH), primary biliary cholangitis/cirrhosis (PBC) and primary sclerosing cholangitis. In March 2019, a phase III trial was initiated for PSC; at that time, the trial was expected to complete in August 2022.

PATENT

Product case WO2013007387 , expiry EU in 2032 and in the US in 2034.

https://patents.google.com/patent/WO2013007387A1/en

Figure imgf000039_0001

PATENT

WO2020150136 claiming 2,6-dichloro-4-fluorophenyl compounds.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020172075&tab=PCTDESCRIPTION&_cid=P20-KEP1ZU-65392-1

WO-2020172075

Novel crystalline forms of cilofexor as FXR agonists useful for treating nonalcoholic steatohepatitis.   Gilead , following a drug acquisition from  Phenex , is developing cilofexor tromethamine (formerly GS-9674), the lead from a program of farnesoid X receptor (FXR; bile acid receptor) agonists, for the potential oral treatment of non-alcoholic steatohepatitis (NASH), primary biliary cholangitis/cirrhosis (PBC) and primary sclerosing cholangitis. In March 2019, a phase III trial was initiated for PSC; at that time, the trial was expected to complete in August 2022. Family members of the cilofexor product case WO2013007387 , expire in the EU in 2032 and in the US in 2034.

solid forms of compounds that bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR. The disclosure further relates to the use of the solid forms of such compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said nuclear receptor by said compounds.

 

[0004] Compounds that bind to the NR1H4 receptor (FXR) can act as agonists or modulators of FXR. FXR agonists are useful for the treatment and/or prophylaxis of diseases and conditions through binding of the NR1H4 receptor. One such FXR agonist is the compound of Formula I:

 

 

I.

 

[0005] Although numerous FXR agonists are known, what is desired in the art are physically stable forms of the compound of Formula I, or pharmaceutically acceptable salt thereof, with desired properties such as good physical and chemical stability, good aqueous solubility and good bioavailability. For example, pharmaceutical compositions are desired that address

challenges of stability, variable pharmacodynamics responses, drug-drug interactions, pH effect, food effects, and oral bioavailability.

 

[0006] Accordingly, there is a need for stable forms of the compound of Formula I with suitable chemical and physical stability for the formulation, therapeutic use, manufacturing, and storage of the compound.

 

[0007] Moreover, it is desirable to develop a solid form of Formula I that may be useful in the synthesis of Formula I. A solid form, such as a crystalline form of a compound of Formula I may be an intermediate to the synthesis of Formula F A solid form may have properties such as bioavailability, stability, purity, and/or manufacturability at certain conditions that may be suitable for medical or pharmaceutical uses.

Description

Cilofexor (GS-9674) is a potent, selective and orally active nonsteroidal FXR agonist with an EC50 of 43 nM. Cilofexor has anti-inflammatory and antifibrotic effects. Cilofexor has the potential for primary sclerosing cholangitis (PSC) and nonalcoholic steatohepatitis (NASH) research[1][2].

IC50 & Target

EC50: 43 nM (FXR)[1]

In Vivo

Cilofexor (GS-9674; 30 mg/kg; oral gavage; once daily; for 10 weeks; male Wistar rats) treatment significantly increases Fgf15 expression in the ileum and decreased Cyp7a1 in the liver in nonalcoholic steatohepatitis (NASH) rats. Liver fibrosis and hepatic collagen expression are significantly reduced. Cilofexor also significantly reduces hepatic stellate cell (HSC) activation and significantly decreases portal pressure, without affecting systemic hemodynamics[3].

Animal Model: Male Wistar rats received a choline-deficient high fat diet (CDHFD)[3]
Dosage: 30 mg/kg
Administration: Oral gavage; once daily; for 10 weeks
Result: Significantly increased Fgf15 expression in the ileum and decreased Cyp7a1 in the liver. Liver fibrosis and hepatic collagen expression were significantly reduced.
Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT02943460 Gilead Sciences
Primary Sclerosing Cholangitis
November 29, 2016 Phase 2
NCT02808312 Gilead Sciences
Nonalcoholic Steatohepatitis (NASH)
July 13, 2016 Phase 1
NCT02781584 Gilead Sciences
Nonalcoholic Steatohepatitis (NASH)|Nonalcoholic Fatty Liver Disease (NAFLD)
July 13, 2016 Phase 2
NCT02943447 Gilead Sciences
Primary Biliary Cholangitis
December 1, 2016 Phase 2
NCT03987074 Gilead Sciences|Novo Nordisk A+S
Nonalcoholic Steatohepatitis
July 29, 2019 Phase 2
NCT03890120 Gilead Sciences
Primary Sclerosing Cholangitis
March 27, 2019 Phase 3
NCT02854605 Gilead Sciences
Nonalcoholic Steatohepatitis (NASH)
October 26, 2016 Phase 2
NCT03449446 Gilead Sciences
Nonalcoholic Steatohepatitis
March 21, 2018 Phase 2
NCT02654002 Gilead Sciences
Nonalcoholic Steatohepatitis (NASH)
January 2016 Phase 1
Patent ID Title Submitted Date Granted Date
US2019142814 Novel FXR (NR1H4) binding and activity modulating compounds 2019-01-15
US2019055273 ACYCLIC ANTIVIRALS 2017-03-09
US10220027 FXR (NR1H4) binding and activity modulating compounds 2017-10-13
US10071108 Methods and pharmaceutical compositions for the treatment of hepatitis b virus infection 2018-02-19
US2018000768 INTESTINAL FXR AGONISM ENHANCES GLP-1 SIGNALING TO RESTORE PANCREATIC BETA CELL FUNCTIONS 2017-09-06
Patent ID Title Submitted Date Granted Date
US9820979 NOVEL FXR (NR1H4) BINDING AND ACTIVITY MODULATING COMPOUNDS 2016-12-05
US9539244 NOVEL FXR (NR1H4) BINDING AND ACTIVITY MODULATING COMPOUNDS 2015-08-12 2015-12-03
US9895380 METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF HEPATITIS B VIRUS INFECTION 2014-09-10 2016-08-04
US2017355693 FXR (NR1H4) MODULATING COMPOUNDS 2017-06-12
US2016376279 FXR AGONISTS AND METHODS FOR MAKING AND USING 2016-09-12
Patent ID Title Submitted Date Granted Date
US9139539 NOVEL FXR (NR1H4) BINDING AND ACTIVITY MODULATING COMPOUNDS 2012-07-12 2014-08-07
US2018133203 METHODS OF TREATING LIVER DISEASE 2017-10-27

ClinicalTrials.gov

CTID Title Phase Status Date
NCT03890120 Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Adults With Primary Sclerosing Cholangitis Phase 3 Recruiting 2020-08-31
NCT02781584 Safety, Tolerability, and Efficacy of Selonsertib, Firsocostat, and Cilofexor in Adults With Nonalcoholic Steatohepatitis (NASH) Phase 2 Recruiting 2020-08-13
NCT03987074 Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Adults With Nonalcoholic Steatohepatitis (NASH) Phase 2 Completed 2020-07-29
NCT02943460 Safety, Tolerability, and Efficacy of Cilofexor in Adults With Primary Sclerosing Cholangitis Without Cirrhosis Phase 2 Completed 2020-06-09
NCT02943447 Safety, Tolerability, and Efficacy of Cilofexor in Adults With Primary Biliary Cholangitis Without Cirrhosis Phase 2 Completed 2020-02-11

ClinicalTrials.gov

CTID Title Phase Status Date
NCT03449446 Safety and Efficacy of Selonsertib, Firsocostat, Cilofexor, and Combinations in Participants With Bridging Fibrosis or Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH) Phase 2 Completed 2019-12-24
NCT02854605 Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Participants With Nonalcoholic Steatohepatitis (NASH) Phase 2 Completed 2019-01-29
NCT02808312 Pharmacokinetics and Pharmacodynamics of GS-9674 in Adults With Normal and Impaired Hepatic Function Phase 1 Completed 2018-10-30
NCT02654002 Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9674, and the Effect of Food on GS-9674 Pharmacokinetics and Pharmacodynamics Phase 1 Completed 2016-07-27

EU Clinical Trials Register

EudraCT Title Phase Status Date
2019-000204-14 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Subjects with Primary Sclerosing Cholangitis Phase 3 Restarted, Ongoing 2019-09-11
2016-002496-10 A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Nonalcoholic Steatohepatitis (NASH) Phase 2 Completed 2017-02-21
2016-002443-42 A Phase 2, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Primary Biliary Cholangitis Without Cirrhosis Phase 2 Completed 2017-01-09
2016-002442-23 A Phase 2, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Primary Sclerosing Cholangitis Without Cirrhosis Phase 2 Completed 2017-01-09

///////////CILOFEXOR, Cilofexor (GS(c)\9674), GS-9674, phase 3

 

C1CC1C2=C(C(=NO2)C3=C(C=CC=C3Cl)Cl)COC4=CC(=C(C=C4)C5(CN(C5)C6=NC=CC(=C6)C(=O)O)O)Cl


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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 AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

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