Novel 5alpha-reductase inhibitors: synthesis, structure-activity studies, and pharmacokinetic profile of phenoxybenzoylphenyl acetic acids
| Autor: | Ola I. A. Salem, Martina Streiber, Alexander Neugebauer, Christiane Scherer, Ruth Maria Maas, Martin Frotscher, Rolf W. Hartmann, Klaus Biemel |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Models Molecular Cell Membrane Permeability Phenylacetates Stereochemistry medicine.medical_treatment Prostatic Hyperplasia Administration Oral Phenylacetic acid Chemical synthesis Benzoates Permeability Steroid Cell Line chemistry.chemical_compound Structure-Activity Relationship 5-alpha Reductase Inhibitors 3-Oxo-5-alpha-Steroid 4-Dehydrogenase Drug Discovery medicine Structure–activity relationship Animals Humans Rats Wistar chemistry.chemical_classification biology Prostate Prostatic Neoplasms Membranes Artificial Bioavailability Rats Isoenzymes Enzyme chemistry Enzyme inhibitor biology.protein Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 49(2) |
| ISSN: | 0022-2623 |
| Popis: | Novel substituted benzoyl benzoic acids and phenylacetic acids 1-14 have been synthesized and evaluated for inhibition of rat and human steroid 5alpha-reductase isozymes 1 and 2. The compounds turned out to be potent and selective human type 2 enzyme inhibitors, exhibiting IC(50) values in the nanomolar range. The phenylacetic acid derivatives were more potent than the analogous benzoic acids. Bromination in the 4-position of the phenoxy moiety led to the strongest inhibitor in this class (12; IC(50) = 5 nM), which was equipotent to finasteride. Since oral absorption is essential for a potential drug, 12 was further examined. In the parallel artificial membrane permeation assay (PAMPA) it turned out to be a good permeator, whereas it was a medium permeator in Caco2 cells. After oral administration (40 mg/kg) to rats a high bioavailability and a biological half-life of 5.5 h were observed, making it a promising candidate for clinical evaluation. |
| Databáze: | OpenAIRE |
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