Design of MKC-442 (Emivirine) Analogues with Improved Activity Against Drug-Resistant HIV Mutants

Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 42; no. 22; pp. 4500 - 4505
Main Authors:	Hopkins, Andrew L, Ren, Jingshan, Tanaka, Hiromichi, Baba, Masanori, Okamato, Mika, Stuart, David I, Stammers, David K
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 04-11-1999
Subjects:	AIDS/HIV Animals Anti-HIV Agents - chemical synthesis Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacology Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Cell Line Crystallography, X-Ray Drug Design Drug Resistance, Microbial emivirine HIV-1 - drug effects HIV-1 - genetics Human immunodeficiency virus Medical sciences Models, Molecular Molecular Conformation Mutation nucleosides Pharmacology. Drug treatments Reverse Transcriptase Inhibitors - chemical synthesis Reverse Transcriptase Inhibitors - chemistry Reverse Transcriptase Inhibitors - pharmacology Uracil - analogs & derivatives Uracil - chemical synthesis Uracil - chemistry Uracil - pharmacology Cyclohexane derivatives RNA-directed DNA polymerase HIV-1 virus Enzyme Transferases Non nucleoside compound Retroviridae Binding site Lentivirus Modeling Biological activity Virus Resistance Nucleotidyltransferases Molecular model Antiviral Benzenic compound Pyrimidine derivatives Human immunodeficiency virus
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Summary:	Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility in adapting to the mutated drug-binding site. GCA-186 had additional 3‘,5‘-dimethyl substituents aimed at forming close contacts with the conserved residue Trp229. Both compounds showed ∼30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X-ray crystallographic structure determination of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series against common drug-resistance mutations.
Bibliography:	ark:/67375/TPS-N1MKSPFD-7 istex:31BC1033D73B407D2ECA6B4DE131A172A52FDCDD ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm990192c