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Novel 5alpha-reductase inhibitors: synthesis, structure-activity studies, and pharmacokinetic profile of phenoxybenzoylphenyl acetic acids.

Salem OI, Frotscher M, Scherer C, Neugebauer A, Biemel K, Streiber M, Maas R, Hartmann RW

Pharmaceutical and Medicinal Chemistry, Saarland University, D-66041 Saarbrücken, Germany.

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.

Published 19 January 2006 in J Med Chem, 49(2): 748-59.
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