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

• Published in: Journal of medicinal chemistry 2013-02, Vol.56 (4), p.1656-1669
• Main Authors: Regueiro-Ren, Alicia, Xue, Qiufen M, Swidorski, Jacob J, Gong, Yi-Fei, Mathew, Marina, Parker, Dawn D, Yang, Zheng, Eggers, Betsy, D’Arienzo, Celia, Sun, Yongnian, Malinowski, Jacek, Gao, Qi, Wu, Dedong, Langley, David R, Colonno, Richard J, Chien, Caly, Grasela, Dennis M, Zheng, Ming, Lin, Pin-Fang, Meanwell, Nicholas A, Kadow, John F
• Format: Article
• Language: English
• Subjects: Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - pharmacology; Caco-2 Cells; Cell Membrane Permeability; Crystallography, X-Ray; HIV-1 - drug effects; HIV-1 - physiology; Humans; Indoles - chemical synthesis; Indoles - pharmacokinetics; Indoles - pharmacology; Microsomes, Liver - metabolism; Piperazines - chemical synthesis; Piperazines - pharmacokinetics; Piperazines - pharmacology; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Pyridines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - pharmacokinetics; Pyrroles - pharmacology; Quantum Theory; Rats; Structure-Activity Relationship; Triazines - chemical synthesis; Triazines - pharmacokinetics; Triazines - pharmacology; Triazoles - chemical synthesis; Triazoles - pharmacokinetics; Triazoles - pharmacology; Virus Attachment - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm3016377

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–l), and N-linked heterocycles (12m–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.