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4-苯甲酰基-1-[(4-甲氧基-1H-吡咯并[2,3-b]吡啶-3-基)氧代乙酰基]-2-(R)-甲基哌嗪（BMS-378806）的发现：一种新型的HIV-1附着抑制剂，可干扰CD4与gp120的相互作用。

Discovery of 4-benzoyl-1-[(4-methoxy-1H- pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2- (R)-methylpiperazine (BMS-378806): a novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions.

作者信息

Wang Tao, Zhang Zhongxing, Wallace Owen B, Deshpande Milind, Fang Haiquan, Yang Zheng, Zadjura Lisa M, Tweedie Donald L, Huang Stella, Zhao Fang, Ranadive Sunanda, Robinson Brett S, Gong Yi-Fei, Ricarrdi Keith, Spicer Timothy P, Deminie Carol, Rose Ronald, Wang Hwei-Gene Heidi, Blair Wade S, Shi Pei-Yong, Lin Pin-Fang, Colonno Richard J, Meanwell Nicholas A

机构信息

Department of Discovery Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.

出版信息

J Med Chem. 2003 Sep 25;46(20):4236-9. doi: 10.1021/jm034082o.

DOI:10.1021/jm034082o
PMID:13678401
Abstract

Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.

摘要

吲哚衍生物1可干扰HIV表面蛋白gp120与宿主细胞受体CD4的相互作用。4-氟衍生物2的效力显著增强，以溶液制剂形式口服给药时在大鼠、犬和食蟹猴体内具有生物利用度。然而，2的水悬浮液生物利用度较差，表明吸收受溶出限制。7-氮杂吲哚衍生物3（BMS-378806）具有改善的药学性质，同时保留了2的HIV-1抑制活性。

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