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

B Narasimhulu Naidu; Michael A Walker; Margaret E Sorenson; Yasutsugu Ueda; John D Matiskella; Timothy P Connolly; Ira B Dicker; Zeyu Lin; Sagarika Bollini; Brian J Terry; Helen Higley; Ming Zheng; Dawn D Parker; Dedong Wu; Stephen Adams; Mark R Krystal; Nicholas A Meanwell

doi:10.1016/j.bmcl.2018.05.027

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

Bioorg Med Chem Lett. 2018 Jul 1;28(12):2124-2130. doi: 10.1016/j.bmcl.2018.05.027. Epub 2018 May 14.

Authors

B Narasimhulu Naidu¹, Michael A Walker², Margaret E Sorenson², Yasutsugu Ueda², John D Matiskella², Timothy P Connolly², Ira B Dicker³, Zeyu Lin³, Sagarika Bollini³, Brian J Terry³, Helen Higley³, Ming Zheng⁴, Dawn D Parker⁴, Dedong Wu⁵, Stephen Adams⁴, Mark R Krystal³, Nicholas A Meanwell²

Affiliations

¹ Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: b.n.naidu@viivhealthcare.com.
² Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
³ Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
⁴ Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
⁵ Materials Chemistry and Crystallography, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.

PMID: 29779976
DOI: 10.1016/j.bmcl.2018.05.027

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.

Keywords: Antiviral activity; HIV-1 integrase; INSTI; Pharmacokinetics; Pyrimidinone carboxamides; Strand transfer inhibitors.

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
HIV / drug effects*
HIV Integrase / metabolism*
HIV Integrase Inhibitors / chemical synthesis
HIV Integrase Inhibitors / chemistry
HIV Integrase Inhibitors / pharmacology*
Humans
Microbial Sensitivity Tests
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology*
Structure-Activity Relationship
Thiazines / chemical synthesis
Thiazines / chemistry
Thiazines / pharmacology*

Substances

Anti-HIV Agents
HIV Integrase Inhibitors
Pyrimidines
Pyrimidinones
Thiazines
BMS-707035
HIV Integrase