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The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Jul 01; Vol. 28 (12), pp. 2124-2130. Date of Electronic Publication: 2018 May 14. - Publication Year :
- 2018
-
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.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 28
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 29779976
- Full Text :
- https://doi.org/10.1016/j.bmcl.2018.05.027