Design, synthesis, and SAR studies of novel and highly active tri-cyclic HIV integrase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2006-08, Vol.16 (15), p.3989-3992
• Main Authors: Jin, Haolun, Cai, Ruby Z., Schacherer, Laura, Jabri, Salman, Tsiang, Manuel, Fardis, Maria, Chen, Xiaowu, Chen, James M., Kim, Choung U.
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Drug Design; HIV; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - pharmacology; Human immunodeficiency virus; Inhibitors; Integrase; Medical sciences; Modeling; Naphthyridines - chemistry; Pharmacology. Drug treatments; Pyrolloquinoline; Structure-Activity Relationship; Tri-cyclic
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.05.016

A novel class of tri-cyclic HIV integrase inhibitors were designed based on the conformational analysis of inhibitors for binding. SAR studies led to the identification of compound 1 exhibiting potent anti-HIV activity with EC 50 = 3.4 nM and favorable physicochemical properties. A novel class of tri-cyclic HIV integrase inhibitors were designed based on conformational analysis of 1,6-naphthyridine carboxamide compound L-870810 and docking the designed inhibitor into the active site of our integrase enzyme model. The efficient syntheses of pyrroloquinoline tri-cyclic analogs are described. The SAR studies resulted in the identification of a lead compound that is more potent and more soluble than L-870810.