title: Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment 6. Preclinical and human pharmacokinetic profiling of BMS-663749, a phosphonooxymethyl prodrug of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043).
abstract: BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and C(max) of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor.
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. john.kadow@bms.com
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
authors.forename: Yasutsugu
authors.initials: Y
authors.lastname: Ueda
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Connolly
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Chen
authors.forename: Kap-Sun
authors.initials: KS
authors.lastname: Yeung
authors.forename: Juliang
authors.initials: J
authors.lastname: Zhu
authors.forename: John A
authors.initials: JA
authors.lastname: Bender
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yang
authors.forename: Dawn
authors.initials: D
authors.lastname: Parker
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Marina
authors.initials: M
authors.lastname: Mathew
authors.forename: Daniel
authors.initials: D
authors.lastname: Morgan
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Caly
authors.initials: C
authors.lastname: Chien
authors.forename: Dennis
authors.initials: D
authors.lastname: Grasela
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004041:Dietary Fats / Q000008:administration & dosage; D004285:Dogs; D018565:Food-Drug Interactions; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D000882:Haplorhini; D006801:Humans; D007211:Indoles; D010755:Organophosphates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019289:Pyruvic Acid; D051381:Rats; D012995:Solubility; D053585:Virus Attachment / Q000187:drug effects*
chemical_list: C573288:(3-((4-benzoylpiperazin-1-yl)(oxo)acetyl)-4,7-dimethoxy-1H-pyrrolo(2,3-c)pyridin-1-yl)methyl dihydrogen phosphate; D019380:Anti-HIV Agents; D004041:Dietary Fats; D007211:Indoles; D010755:Organophosphates; D010879:Piperazines; D011355:Prodrugs; D019289:Pyruvic Acid; C509651:BMS-488043