Tricyclic HIV integrase inhibitors: VI. SAR studies of ‘benzyl flipped’ C3-substituted pyrroloquinolines

• Published in: Bioorganic & medicinal chemistry letters 2009-02, Vol.19 (4), p.1187-1190
• Main Authors: Metobo, Sammy, Mish, Michael, Jin, Haolun, Jabri, Salman, Lansdown, Rachael, Chen, Xiaowu, Tsiang, Manuel, Wright, Matthew, Kim, Choung U.
• Format: Article
• Language: English
• Subjects: Administration, Oral; AIDS; Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; C3 Benzyl SAR; Dogs; Drug Design; HIV; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; Human immunodeficiency virus; Humans; Integase inhibitors; Molecular Structure; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Rats; Structure-Activity Relationship; Tricyclic pyrroloquinoline
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.12.079

A series of C3-halobenzyl-substituted tricyclic integrase inhibitors was prepared. Excellent cell-based inhibitor potency was observed, and selected leads in this new series showed good bioavailability and long t 1/2 in animal PK studies. A series of C3 halobenzyl-substituted tricyclic HIV integrase inhibitors was prepared. Improvement in cell-based inhibitor potency was observed in comparison to previously disclosed tricyclic pyrroloquinolines carrying the ‘halobenzyl tail’ at the lactam nitrogen. Animal PK for several of the C3-substituted inhibitors was examined, with a dihaloaryl analog achieving good balance in protein-shifted EC 50 and t 1/2 in animal PK studies.