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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

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

doi

10.1021/jm050728w

keywords:

subject

Has Abstract

pub_date

2006-01-26 00:00:00

pages

748-59

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

49

pub_type

杂志文章

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