title: Discovery and early clinical evaluation of BMS-605339, a potent and orally efficacious tripeptidic acylsulfonamide NS3 protease inhibitor for the treatment of hepatitis C virus infection.
abstract: The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
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: Alan Xiangdong
authors.initials: AX
authors.lastname: Wang
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.forename: Li-Qiang
authors.initials: LQ
authors.lastname: Sun
authors.forename: Keith D
authors.initials: KD
authors.lastname: Combrink
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Campbell
authors.forename: Jie
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authors.lastname: Chen
authors.forename: Yong
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authors.lastname: Sin
authors.forename: Brian L
authors.initials: BL
authors.lastname: Venables
authors.forename: Sing-Yuen
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authors.lastname: Sit
authors.forename: Yan
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authors.lastname: Chen
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authors.lastname: Cocuzza
authors.forename: Donna M
authors.initials: DM
authors.lastname: Bilder
authors.forename: Stanley
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authors.lastname: D'Andrea
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authors.lastname: Zheng
authors.forename: Piyasena
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authors.lastname: Hewawasam
authors.forename: Min
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authors.lastname: Ding
authors.forename: Jan
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authors.lastname: Thuring
authors.forename: Jianqing
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authors.lastname: Li
authors.forename: Dennis
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authors.lastname: Hernandez
authors.forename: Fei
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authors.lastname: Yu
authors.forename: Paul
authors.initials: P
authors.lastname: Falk
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Zhai
authors.forename: Amy K
authors.initials: AK
authors.lastname: Sheaffer
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Chen
authors.forename: Min S
authors.initials: MS
authors.lastname: Lee
authors.forename: Diana
authors.initials: D
authors.lastname: Barry
authors.forename: Jay O
authors.initials: JO
authors.lastname: Knipe
authors.forename: Wenying
authors.initials: W
authors.lastname: Li
authors.forename: Yong-Hae
authors.initials: YH
authors.lastname: Han
authors.forename: Susan
authors.initials: S
authors.lastname: Jenkins
authors.forename: Christoph
authors.initials: C
authors.lastname: Gesenberg
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sinz
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Santone
authors.forename: Tatyana
authors.initials: T
authors.lastname: Zvyaga
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Rajamani
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Klei
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
authors.forename: Eric
authors.initials: E
authors.lastname: Hughes
authors.forename: Caly
authors.initials: C
authors.lastname: Chien
authors.forename: Stephen
authors.initials: S
authors.lastname: Adams
authors.forename: Paul C
authors.initials: PC
authors.lastname: Levesque
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 / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D004285:Dogs; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000627:therapeutic use*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D013449:Sulfonamides / 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; C583042:BMS-605339; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases