title: Discovery of substituted 3-(phenylamino)benzoic acids as potent and selective inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3).
abstract: Aldo-keto reductase 1C3 (AKR1C3) also known as type 5 17β-hydroxysteroid dehydrogenase has been implicated as one of the key enzymes driving the elevated intratumoral androgen levels observed in castrate resistant prostate cancer (CRPC). AKR1C3 inhibition therefore presents a rational approach to managing CRPC. Inhibitors should be selective for AKR1C3 over other AKR1C enzymes involved in androgen metabolism. We have synthesized 2-, 3-, and 4-(phenylamino)benzoic acids and identified 3-(phenylamino)benzoic acids that have nanomolar affinity and exhibit over 200-fold selectivity for AKR1C3 versus other AKR1C isoforms. The AKR1C3 inhibitory potency of the 4'-substituted 3-(phenylamino)benzoic acids shows a linear correlation with both electronic effects of substituents and the pK(a) of the carboxylic acid and secondary amine groups, which are interdependent. These compounds may be useful in treatment and/or prevention of CRPC as well as understanding the role of AKR1C3 in endocrinology.
authors.affiliation: Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104-6084, USA.
authors.forename: Adegoke O
authors.initials: AO
authors.lastname: Adeniji
authors.forename: Barry M
authors.initials: BM
authors.lastname: Twenter
authors.forename: Michael C
authors.initials: MC
authors.lastname: Byrns
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Winkler
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Penning
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019817:Benzoic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D015394:Molecular Structure
chemical_list: D000814:Aniline Compounds; D019817:Benzoic Acid; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3