title: Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.
abstract: The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).
authors: Li-Qiang
authors: LQ
authors: Sun
authors: Eric
authors: E
authors: Mull
authors: Barbara
authors: B
authors: Zheng
authors: Stanley
authors: S
authors: D'Andrea
authors: Qian
authors: Q
authors: Zhao
authors: Alan Xiangdong
authors: AX
authors: Wang
authors: Ny
authors: N
authors: Sin
authors: Brian L
authors: BL
authors: Venables
authors: Sing-Yuen
authors: SY
authors: Sit
authors: Yan
authors: Y
authors: Chen
authors: Jie
authors: J
authors: Chen
authors: Anthony
authors: A
authors: Cocuzza
authors: Donna M
authors: DM
authors: Bilder
authors: Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States.
authors: Arvind
authors: A
authors: Mathur
authors: Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States.
authors: Richard
authors: R
authors: Rampulla
authors: Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States.
authors: Bang-Chi
authors: BC
authors: Chen
authors: Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
authors: Theerthagiri
authors: T
authors: Palani
authors: Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
authors: Sivakumar
authors: S
authors: Ganesan
authors: Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
authors: Pirama Nayagam
authors: PN
authors: Arunachalam
authors: Paul
authors: P
authors: Falk
authors: Steven
authors: S
authors: Levine
authors: Chaoqun
authors: C
authors: Chen
authors: Jacques
authors: J
authors: Friborg
authors: Fei
authors: F
authors: Yu
authors: Dennis
authors: D
authors: Hernandez
authors: Amy K
authors: AK
authors: Sheaffer
authors: Jay O
authors: JO
authors: Knipe
authors: Yong-Hae
authors: YH
authors: Han
authors: Richard
authors: R
authors: Schartman
authors: Maria
authors: M
authors: Donoso
authors: Kathy
authors: K
authors: Mosure
authors: Michael W
authors: MW
authors: Sinz
authors: Tatyana
authors: T
authors: Zvyaga
authors: Ramkumar
authors: R
authors: Rajamani
authors: Kevin
authors: K
authors: Kish
authors: Jeffrey
authors: J
authors: Tredup
authors: Herbert E
authors: HE
authors: Klei
authors: Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors: Qi
authors: Q
authors: Gao
authors: Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors: Alicia
authors: A
authors: Ng
authors: Luciano
authors: L
authors: Mueller
authors: Dennis M
authors: DM
authors: Grasela
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors: Stephen
authors: S
authors: Adams
authors: James
authors: J
authors: Loy
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors: Paul C
authors: PC
authors: Levesque
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors: Huabin
authors: H
authors: Sun
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors: Hong
authors: H
authors: Shi
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors: Lucy
authors: L
authors: Sun
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors: William
authors: W
authors: Warner
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors: Danshi
authors: D
authors: Li
authors: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors: Jialong
authors: J
authors: Zhu
authors: Ying-Kai
authors: YK
authors: Wang
authors: Hua
authors: H
authors: Fang
authors: Mark I
authors: MI
authors: Cockett
authors: Nicholas A
authors: NA
authors: Meanwell
authors: Fiona
authors: F
authors: McPhee
authors: Paul M
authors: PM
authors: Scola
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D007546:Isoquinolines / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D017207:Rats, Sprague-Dawley; D012093:Replicon; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D007546:Isoquinolines; D009842:Oligopeptides; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C000621127:BMS-890068; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C571889:asunaprevir