1. The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor.
- Author
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Naidu BN, Walker MA, Sorenson ME, Ueda Y, Matiskella JD, Connolly TP, Dicker IB, Lin Z, Bollini S, Terry BJ, Higley H, Zheng M, Parker DD, Wu D, Adams S, Krystal MR, and Meanwell NA
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, HIV Integrase Inhibitors chemical synthesis, HIV Integrase Inhibitors chemistry, Humans, Microbial Sensitivity Tests, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Pyrimidinones chemical synthesis, Pyrimidinones chemistry, Structure-Activity Relationship, Thiazines chemical synthesis, Thiazines chemistry, Anti-HIV Agents pharmacology, Drug Discovery, HIV drug effects, HIV Integrase metabolism, HIV Integrase Inhibitors pharmacology, Pyrimidines pharmacology, Pyrimidinones pharmacology, Thiazines pharmacology
- Abstract
BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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