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2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Apr 08; Vol. 64 (7), pp. 4239-4256. Date of Electronic Publication: 2021 Mar 18. - Publication Year :
- 2021
-
Abstract
- There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead K-5a2 led to the identification of a potent inhibitor 16c . 16c yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of 16c toward the NNRTI-adjacent site as a lead development strategy. Furthermore, 16c demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of 16c as a promising anti-HIV-1 drug candidate.
- Subjects :
- Animals
Anti-HIV Agents chemical synthesis
Anti-HIV Agents metabolism
Crystallography, X-Ray
Drug Design
HEK293 Cells
HIV Reverse Transcriptase metabolism
HIV-1 genetics
Humans
Mice
Microbial Sensitivity Tests
Molecular Structure
Mutation
Protein Binding
Pyrimidines chemical synthesis
Pyrimidines metabolism
Rats, Sprague-Dawley
Reverse Transcriptase Inhibitors chemical synthesis
Reverse Transcriptase Inhibitors metabolism
Structure-Activity Relationship
Rats
Anti-HIV Agents pharmacology
HIV Reverse Transcriptase antagonists & inhibitors
HIV-1 drug effects
Pyrimidines pharmacology
Reverse Transcriptase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33734714
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00268