3t1a

Publication Abstract from PubMed

Highly active anti-retroviral therapy (HAART) significantly reduces HIV viral load and has led to a dramatic decrease in AIDS related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought which are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker and each of these conformations were rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2 provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had comparable potency to the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type (wt) and the clinically relevant mutant strains.

Design and Synthesis of conformationally Constrained Inhibitors of Non-Nucleoside Reverse Transcriptase.,Gomez R, Jolly S, Williams TM, Vacca JP, Torrent M, McGaughey G, Lai MT, Felock PJ, Munshi V, Distefano D, Flynn JA, Miller MD, Yan Y, Reid JC, Sanchez R, Liang Y, Paton B, Wan BL, Anthony NJ J Med Chem. 2011 Oct 10. PMID:21985673^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.