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-

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• 作者：John F. Kadow ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2048-2056
• 全文大小：353K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

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.