title: Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase.
abstract: Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.
authors.affiliation: Discovery Chemistry, ‡Molecular Discovery Technologies, Molecular Structure & Design, §Molecular Discovery Technologies, Protein Science, ∥Pharmaceutical Candidate Optimization, ⊥Discovery Virology, Disease Sciences and Biologics, #Leads Discovery and Optimization, ▽Materials Science, Drug Product Science and Technology, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gentles
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.forename: John A
authors.initials: JA
authors.lastname: Bender
authors.forename: Carl P
authors.initials: CP
authors.lastname: Bergstrom
authors.forename: Katharine
authors.initials: K
authors.lastname: Grant-Young
authors.forename: Piyasena
authors.initials: P
authors.lastname: Hewawasam
authors.forename: Thomas
authors.initials: T
authors.lastname: Hudyma
authors.forename: Scott
authors.initials: S
authors.lastname: Martin
authors.forename: Andrew
authors.initials: A
authors.lastname: Nickel
authors.forename: Alicia
authors.initials: A
authors.lastname: Regueiro-Ren
authors.forename: Yong
authors.initials: Y
authors.lastname: Tu
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yang
authors.forename: Kap-Sun
authors.initials: KS
authors.lastname: Yeung
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Zheng
authors.forename: Sam
authors.initials: S
authors.lastname: Chao
authors.forename: Jung-Hui
authors.initials: JH
authors.lastname: Sun
authors.forename: Brett R
authors.initials: BR
authors.lastname: Beno
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Camac
authors.forename: Chong-Hwan
authors.initials: CH
authors.lastname: Chang
authors.forename: Mian
authors.initials: M
authors.lastname: Gao
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morin
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.forename: Jeff
authors.initials: J
authors.lastname: Tredup
authors.forename: John
authors.initials: J
authors.lastname: Wan
authors.forename: Mark R
authors.initials: MR
authors.lastname: Witmer
authors.forename: Dianlin
authors.initials: D
authors.lastname: Xie
authors.forename: Umesh
authors.initials: U
authors.lastname: Hanumegowda
authors.forename: Jay
authors.initials: J
authors.lastname: Knipe
authors.forename: Kathy
authors.initials: K
authors.lastname: Mosure
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Santone
authors.forename: Dawn D
authors.initials: DD
authors.lastname: Parker
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Zhuo
authors.forename: Julie
authors.initials: J
authors.lastname: Lemm
authors.forename: Mengping
authors.initials: M
authors.lastname: Liu
authors.forename: Lenore
authors.initials: L
authors.lastname: Pelosi
authors.forename: Karen
authors.initials: K
authors.lastname: Rigat
authors.forename: Stacey
authors.initials: S
authors.lastname: Voss
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Ying-Kai
authors.initials: YK
authors.lastname: Wang
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Susan B
authors.initials: SB
authors.lastname: Roberts
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Alicia
authors.initials: A
authors.lastname: Ng
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001552:Benzazepines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001552:Benzazepines; D004791:Enzyme Inhibitors; D007211:Indoles; D017361:Viral Nonstructural Proteins; C587012:8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase