Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment. 5. An Evolution from Indole to Azaindoles Leading to the Discovery of 1-(4-Benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a Drug Candidate That Demonstrates Antiviral Activity in HIV-1-Infected Subjects

• Published in: Journal of medicinal chemistry Vol. 52; no. 23; pp. 7778 - 7787
• Main Authors: Wang, Tao, Yin, Zhiwei, Zhang, Zhongxing, Bender, John A, Yang, Zhong, Johnson, Graham, Yang, Zheng, Zadjura, Lisa M, D’Arienzo, Celia J, DiGiugno Parker, Dawn, Gesenberg, Christophe, Yamanaka, Gregory A, Gong, Yi-Fei, Ho, Hsu-Tso, Fang, Hua, Zhou, Nannan, McAuliffe, Brian V, Eggers, Betsy J, Fan, Li, Nowicka-Sans, Beata, Dicker, Ira B, Gao, Qi, Colonno, Richard J, Lin, Pin-Fang, Meanwell, Nicholas A, Kadow, John F
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.12.2009; Amer Chemical Soc
• Subjects: Animals; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Drug Discovery; HIV Infections - drug therapy; HIV-1 - drug effects; HIV-1 - physiology; Humans; Indoles - chemistry; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperazines - chemistry; Piperazines - pharmacokinetics; Piperazines - pharmacology; Piperazines - therapeutic use; Rats; Reproducibility of Results; Science & Technology; Virus Attachment - drug effects; SUBSTITUTION PATTERNS; GP120 ENVELOPE; ENTRY INHIBITORS; CONFORMATIONAL-CHANGES; CD4 RECEPTOR-BINDING; MOLECULE; RESISTANCE; TARGETS; PART 2; VIRAL ENVELOPE; Ketoamide; Intravenous administration; Rat; HIV-1 virus; Nitrogen heterocycle; Structure activity relation; Bicyclic compound; Antiviral; Chemical synthesis; Immunopathology; Rodentia; Oral administration; Retroviridae; AIDS; Bioavailability; Immune deficiency; Lentivirus; In vitro; Infection; Virus; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Viral disease; Animal; Carboxamide; Human immunodeficiency virus; Piperazine derivatives; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm900843g

Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.