Cycloalkylpyranones and Cycloalkyldihydropyrones as HIV Protease Inhibitors: Exploring the Impact of Ring Size on Structure−Activity Relationships
| Autor: | R. R. Hinshaw, M.‐M. Horng, W. Jeffrey Howe, David J. Anderson, and Steve R. Turner, Chong Kt, Steve A. Mizsak, Jeanette Kay Morris, Paul K. Tomich, Strohbach Joseph Walter, Karen Rene Romines |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Models
Molecular Molecular model Anti-HIV Agents Protein Conformation Stereochemistry medicine.medical_treatment Crystallography X-Ray Ring (chemistry) Structure-Activity Relationship Meta chemistry.chemical_compound HIV Protease Drug Discovery medicine Aspartic Acid Endopeptidases HIV Protease Inhibitor chemistry.chemical_classification Sulfonamides Binding Sites Protease Molecular Structure Chemistry HIV Protease Inhibitors Pyrone Ring size Cyclization Pyrones Molecular Medicine Lactone |
| Zdroj: | Journal of Medicinal Chemistry. 39:4125-4130 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm960296c |
| Popis: | Previously, 3-substituted cycloalkylpyranones, such as 2d, have proven to be effective inhibitors of HIV protease. In an initial series of 3-(1-phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We became interested in exploring the influence of other structural changes, such as substitution on the phenyl ring and saturation of the 5,6-double bond, on the cycloalkyl ring size structure-activity relationship (SAR). Saturation of the 5,6-double bond in the pyrone ring significantly impacts the SAR, altering the optimal ring size from eight to six. Substitution of a sulfonamide at the meta position of the phenyl ring dramatically increases the potency of these inhibitors, but it does not change the optimal ring size in either the cycloalkylpyranone or the cycloalkyldihydropyrone series. This work has led to the identification of compounds with superb binding affinity for the HIV protease (Ki values in the 10-50 pM range). In addition, the cycloalkyldihydropyrones showed excellent antiviral activity in cell culture, with ED50 values as low as 1 microM. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|