title: Inhibitors of HIV-1 attachment. Part 11: the discovery and structure-activity relationships associated with 4,6-diazaindole cores.
abstract: A series of HIV-1 attachment inhibitors containing a 4,6-diazaindole core were examined in an effort to identify a compound which improved upon the potency and oral exposure of BMS-488043 (2). BMS-488043 (2) is a 6-azaindole-based HIV-1 attachment inhibitor which established proof-of-concept for this mechanism in human clinical studies but required high doses and concomitant administration of a high fat meal to achieve efficacious exposures. Based on previous studies in indole and azaindole scaffolds, SAR investigation was concentrated around the key 7-position in the 4,6-diazaindole series and led to the discovery of molecules with 5- to 20-fold increases in potency and three- to seven-fold increases in exposure over 2 in a rat PK studies.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. john.bender@bms.com
authors.forename: John A
authors.initials: JA
authors.lastname: Bender
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yang
authors.forename: Betsy
authors.initials: B
authors.lastname: Eggers
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Gong
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
authors.forename: Dawn D
authors.initials: DD
authors.lastname: Parker
authors.forename: Sandhya
authors.initials: S
authors.lastname: Rahematpura
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics; D019289:Pyruvic Acid; D051381:Rats; D013329:Structure-Activity Relationship; D053585:Virus Attachment / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D001372:Aza Compounds; D007211:Indoles; D010879:Piperazines; D019289:Pyruvic Acid; C509651:BMS-488043