Details

Autor(en) / Beteiligte

• Salem, Ola I. A
• Frotscher, Martin
• Scherer, Christiane
• Neugebauer, Alexander
• Biemel, Klaus
• Streiber, Martina
• Maas, Ruth
• Hartmann, Rolf W

Titel

Novel 5α-Reductase Inhibitors:  Synthesis, Structure−Activity Studies, and Pharmacokinetic Profile of Phenoxybenzoylphenyl Acetic Acids

Ist Teil von

• Journal of medicinal chemistry, 2006-01, Vol.49 (2), p.748-759

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2006

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Novel substituted benzoyl benzoic acids and phenylacetic acids 1 − 14 have been synthesized and evaluated for inhibition of rat and human steroid 5α-reductase isozymes 1 and 2. The compounds turned out to be potent and selective human type 2 enzyme inhibitors, exhibiting IC50 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; IC50 = 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.