The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor

Bioorganic & Medicinal Chemistry Letters
B Narasimhulu NaiduNicholas A Meanwell

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.

Citations

Jan 23, 2020·Current HIV/AIDS Reports·Jay TrivediSiddappa N Byrareddy
Sep 3, 2019·Frontiers in Microbiology·Michał S BarskiGoedele N Maertens
Aug 31, 2019·The Journal of Biological Chemistry·Alan N Engelman
Sep 6, 2020·Bioorganic & Medicinal Chemistry Letters·Prasanna SivaprakasamB Narasimhulu Naidu
Jan 1, 2021·Journal of Medicinal Chemistry·Kerstin HiesingerMikhail Krasavin
Jul 21, 2020·Journal of Medicinal Chemistry·Shikha KumariPaul C Trippier
Aug 24, 2021·European Journal of Medicinal Chemistry·Yue WangRenhua Fan

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