Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment. 12. Structure鈥揂ctivity Relationships Associated with 4-Fluoro-6-azaindole Derivatives Leading to the Identification of 1-(4-Benzoy

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• 作者：Alicia Regueiro-Ren ; Qiufen M. Xue ; Jacob J. Swidorski ; Yi-Fei Gong ; Marina Mathew ; Dawn D. Parker ; Zheng Yang ; Betsy Eggers ; Celia D鈥橝rienzo ; Yongnian Sun ; Jacek Malinowski ; Qi Gao ; Dedong Wu ; David R. Langley ; Richard J. Colonno ; Caly Chien ; Dennis M. Grasela ; Ming Zheng ; Pin-Fang Lin ; Nicholas A. Meanwell ; John F. Kadow
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 28, 2013
• 年：2013
• 卷：56
• 期：4
• 页码：1656-1669
• 全文大小：470K
• 年卷期：v.56,no.4(February 28, 2013)
• ISSN：1520-4804

文摘

A series of highly potent HIV-1 attachment inhibitors with 4-fluoro-6-azaindole core heterocycles that target the viral envelope protein gp120 has been prepared. Substitution in the 7-position of the azaindole core with amides (12a,b), C-linked heterocycles (12c鈥?b>l), and N-linked heterocycles (12m鈥?b>u) provided compounds with subnanomolar potency in a pseudotype infectivity assay and good pharmacokinetic profiles in vivo. A predictive model was developed from the initial SAR in which the potency of the analogues correlated with the ability of the substituent in the 7-position of the azaindole to adopt a coplanar conformation by either forming internal hydrogen bonds or avoiding repulsive substitution patterns. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-[1,2,3]triazol-1-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-585248, 12m) exhibited much improved in vitro potency and pharmacokinetic properties than the previous clinical candidate BMS-488043 (1). The predicted low clearance in humans, modest protein binding, and good potency in the presence of 40% human serum for 12m led to its selection for human clinical studies.