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)

Journal of Medicinal Chemistry
John F KadowDennis Grasela

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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Citations

Mar 18, 2016·ACS Medicinal Chemistry Letters·Zhao DangChin-Ho Chen
Oct 15, 2014·Expert Opinion on Therapeutic Patents·Xiao LiXinyong Liu
Oct 29, 2015·Journal of Medicinal Chemistry·Peng ZhanXinyong Liu
Apr 28, 2018·Nature Reviews. Drug Discovery·Jarkko RautioMichael J Hageman
Dec 4, 2019·Journal of Computer-aided Molecular Design·Radhika VangalaVijjulatha Manga
Feb 3, 2021·Journal of Medicinal Chemistry·Pei-Pei KungLuke Zehnder
Dec 23, 2017·Journal of Medicinal Chemistry·Nicholas A MeanwellJohn F Kadow

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