title: Novel 5alpha-reductase inhibitors: synthesis, structure-activity studies, and pharmacokinetic profile of phenoxybenzoylphenyl acetic acids.
abstract: 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.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, D-66041 Saarbrücken, Germany.
authors.forename: Ola I A
authors.initials: OI
authors.lastname: Salem
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
authors.forename: Christiane
authors.initials: C
authors.lastname: Scherer
authors.forename: Alexander
authors.initials: A
authors.lastname: Neugebauer
authors.forename: Klaus
authors.initials: K
authors.lastname: Biemel
authors.forename: Martina
authors.initials: M
authors.lastname: Streiber
authors.forename: Ruth
authors.initials: R
authors.lastname: Maas
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D058891:5-alpha Reductase Inhibitors; D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002460:Cell Line; D002463:Cell Membrane Permeability; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008567:Membranes, Artificial; D008958:Models, Molecular; D010539:Permeability; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011467:Prostate / Q000201:enzymology; D011470:Prostatic Hyperplasia / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D058891:5-alpha Reductase Inhibitors; D001565:Benzoates; D007527:Isoenzymes; D008567:Membranes, Artificial; D010648:Phenylacetates; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C476566:steroid-5alpha-reductase type 1; C476567:steroid-5alpha-reductase type 2