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Publicatie

2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies

Tijdschriftbijdrage - Tijdschriftartikel

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.
Tijdschrift: Journal of Medicinal Chemistry
ISSN: 0022-2623
Issue: 7
Volume: 64
Pagina's: 4239 - 4256
Jaar van publicatie:2021
BOF-keylabel:ja
IOF-keylabel:ja
BOF-publication weight:10
CSS-citation score:4
Auteurs:International
Authors from:Higher Education
Toegankelijkheid:Closed