The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor. Issue 12 (1st July 2018)

• Record Type: Journal Article
• Authors: Naidu, B. Narasimhulu; Walker, Michael A.; Sorenson, Margaret E.; Ueda, Yasutsugu; Matiskella, John D.; Connolly, Timothy P.; Dicker, Ira B.; Lin, Zeyu; Bollini, Sagarika; Terry, Brian J.; Higley, Helen; Zheng, Ming; Parker, Dawn D.; Wu, Dedong; Adams, Stephen; Krystal, Mark R.; Meanwell, Nicholas A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 12(2018)
• Page Start: 2124
• Page End: 2130
• Publication Date: 2018-07-01
• Subjects: HIV-1 integrase -- Strand transfer inhibitors -- INSTI -- Pyrimidinone carboxamides -- Antiviral activity -- Pharmacokinetics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.05.027
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Synthesis and antiviral activities of series of pyrimidinone carboxamide described. BMS-707035 is a potent HIV-1 integrase strand transfer inhibitor. It displayed good preclinical profiles; advanced to clinical trials. Development halted due to the findings in 12-month dog safety assessment study. 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.