title: The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection.
abstract: The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut, 06492, United States.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Scola
authors.forename: Li-Qiang
authors.initials: LQ
authors.lastname: Sun
authors.forename: Alan Xiangdong
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authors.lastname: Wang
authors.forename: Jie
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authors.lastname: Chen
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authors.lastname: Sin
authors.forename: Brian L
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authors.lastname: Venables
authors.forename: Sing-Yuen
authors.initials: SY
authors.lastname: Sit
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authors.lastname: Chen
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authors.lastname: Cocuzza
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authors.lastname: Bilder
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authors.forename: Barbara
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authors.lastname: Hewawasam
authors.forename: Yong
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authors.lastname: Falk
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authors.lastname: Levine
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authors.lastname: Chen
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authors.lastname: Yu
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authors.lastname: Sheaffer
authors.forename: Guangzhi
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authors.lastname: Zhai
authors.forename: Diana
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authors.lastname: Barry
authors.forename: Jay O
authors.initials: JO
authors.lastname: Knipe
authors.forename: Yong-Hae
authors.initials: YH
authors.lastname: Han
authors.forename: Richard
authors.initials: R
authors.lastname: Schartman
authors.forename: Maria
authors.initials: M
authors.lastname: Donoso
authors.forename: Kathy
authors.initials: K
authors.lastname: Mosure
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sinz
authors.forename: Tatyana
authors.initials: T
authors.lastname: Zvyaga
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.forename: Ramkumar
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authors.lastname: Rajamani
authors.forename: Kevin
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authors.lastname: Kish
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Tredup
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Klei
authors.forename: Qi
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authors.lastname: Gao
authors.forename: Luciano
authors.initials: L
authors.lastname: Mueller
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Dennis M
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authors.lastname: Grasela
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Adams
authors.forename: James
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authors.lastname: Loy
authors.forename: Paul C
authors.initials: PC
authors.lastname: Levesque
authors.forename: Huabin
authors.initials: H
authors.lastname: Sun
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.forename: Lucy
authors.initials: L
authors.lastname: Sun
authors.forename: William
authors.initials: W
authors.lastname: Warner
authors.forename: Danshi
authors.initials: D
authors.lastname: Li
authors.forename: Jialong
authors.initials: J
authors.lastname: Zhu
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D004285:Dogs; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007546:Isoquinolines / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D013449:Sulfonamides / Q000097:blood / Q000737:chemistry / 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; D011480:Protease Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C571889:asunaprevir