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Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 May 14; Vol. 63 (9), pp. 4837-4848. Date of Electronic Publication: 2020 Apr 22. - Publication Year :
- 2020
-
Abstract
- The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3- d ]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9a <superscript>res</superscript> strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats ( F = 37.06%) and safety in mice (LD <subscript>50</subscript> > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
- Subjects :
- Animals
Anti-HIV Agents metabolism
Anti-HIV Agents pharmacokinetics
Cell Line, Tumor
Enzyme Assays
HIV Reverse Transcriptase genetics
HIV Reverse Transcriptase metabolism
HIV-1 enzymology
Humans
Mice
Microbial Sensitivity Tests
Microsomes, Liver metabolism
Molecular Docking Simulation
Mutation
Protein Binding
Pyrimidines metabolism
Pyrimidines pharmacokinetics
Reverse Transcriptase Inhibitors metabolism
Reverse Transcriptase Inhibitors pharmacokinetics
Thiophenes metabolism
Thiophenes pharmacokinetics
Anti-HIV Agents pharmacology
HIV Reverse Transcriptase antagonists & inhibitors
HIV-1 drug effects
Pyrimidines pharmacology
Reverse Transcriptase Inhibitors pharmacology
Thiophenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32293182
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.0c00117