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)

  • J Med Chem. 2012 Mar 8;55(5):2048-56. doi: 10.1021/jm201218m.
John F Kadow  1 ,  Yasutsugu Ueda ,  Nicholas A Meanwell ,  Timothy P Connolly ,  Tao Wang ,  Chung-Pin Chen ,  Kap-Sun Yeung ,  Juliang Zhu ,  John A Bender ,  Zhong Yang ,  Dawn Parker ,  Pin-Fang Lin ,  Richard J Colonno ,  Marina Mathew ,  Daniel Morgan ,  Ming Zheng ,  Caly Chien ,  Dennis Grasela
Affiliations
  • 1. Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. [email protected]
PMID: 22356441 DOI: 10.1021/jm201218m
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.

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