2. Academic Validation
  3. The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor

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.
B Narasimhulu Naidu 1,  Michael A Walker 2,  Margaret E Sorenson 2,  Yasutsugu Ueda 2,  John D Matiskella 2,  Timothy P Connolly 2,  Ira B Dicker 3,  Zeyu Lin 3,  Sagarika Bollini 3,  Brian J Terry 3,  Helen Higley 3,  Ming Zheng 4,  Dawn D Parker 4,  Dedong Wu 5,  Stephen Adams 4,  Mark R Krystal 3,  Nicholas A Meanwell 2
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: [email protected].
  • 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.

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