title: Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 5. An evolution from indole to azaindoles leading to the discovery of 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a drug candidate that demonstrates antiviral activity in HIV-1-infected subjects.
abstract: Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.
authors.affiliation: Departments of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. tao.wang@bms.com
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yin
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Zhang
authors.forename: John A
authors.initials: JA
authors.lastname: Bender
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yang
authors.forename: Graham
authors.initials: G
authors.lastname: Johnson
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Zadjura
authors.forename: Celia J
authors.initials: CJ
authors.lastname: D'Arienzo
authors.forename: Dawn
authors.initials: D
authors.lastname: DiGiugno Parker
authors.forename: Christophe
authors.initials: C
authors.lastname: Gesenberg
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yamanaka
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Gong
authors.forename: Hsu-Tso
authors.initials: HT
authors.lastname: Ho
authors.forename: Hua
authors.initials: H
authors.lastname: Fang
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.forename: Brian V
authors.initials: BV
authors.lastname: McAuliffe
authors.forename: Betsy J
authors.initials: BJ
authors.lastname: Eggers
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Beata
authors.initials: B
authors.lastname: Nowicka-Sans
authors.forename: Ira B
authors.initials: IB
authors.lastname: Dicker
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D055808:Drug Discovery; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019289:Pyruvic Acid; D051381:Rats; D015203:Reproducibility of Results; D053585:Virus Attachment / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; C477855:BMS-378806; D007211:Indoles; D010879:Piperazines; D019289:Pyruvic Acid; C509651:BMS-488043