Novel 1,5-Diphenylpyrazole Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors with Enhanced Activity versus the Delavirdine-Resistant P236L Mutant: Lead Identification and SAR of 3- and 4-Substituted Derivatives
| Autor: | S M Swaney, Michael J. Genin, S M Poppe, Donna L. Romero, Carolyn Biles, Keiser Bj, Y. Yagi, W G Tarpley |
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| Rok vydání: | 2000 |
| Předmět: |
chemistry.chemical_classification
biology Anti-HIV Agents Stereochemistry Mutant Drug Resistance Microbial Chemical synthesis HIV Reverse Transcriptase Reverse transcriptase Structure-Activity Relationship Enzyme Viral replication chemistry Enzyme inhibitor Mutation Drug Discovery biology.protein medicine Pyrazoles Reverse Transcriptase Inhibitors Molecular Medicine Delavirdine IC50 medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 43:1034-1040 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm990383f |
| Popis: | Through computationally directed broad screening, a novel 1, 5-diphenylpyrazole (DPP) class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered. Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC(50) = 2.3 microM) and delavirdine-resistant P236L (IC(50) = 1.1 microM) reverse transcriptase (RT). Also, PNU-32945 has an ED(50) for inhibition of viral replication in cell cultures of 0.1 microM and was shown to be noncytotoxic with a CC(50)10 microM. Structure-activity relationship studies on the 3- and 4-positions of PNU-32945 led to interesting selectivity and activity within the class. In particular, the 3-hydroxyethyl-4-ethyl congener 29 is a potent inhibitor of the P236L mutant (IC(50) = 0.65 microM), whereas it is essentially inactive versus the wild-type enzyme (IC(50)50 microM). Furthermore, this compound was significantly more active versus the P236L mutant than delavirdine. The synthesis and RT inhibitory activity of various 3- and 4-substituted analogues are discussed. |
| Databáze: | OpenAIRE |
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