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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Development of potent and selective inhibitors of aldo-keto reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase) based on N-phenyl-aminobenzoates and their structure-activity relationships.

Authors: Adeniji, Adegoke O; Twenter, Barry M; Byrns, Michael C; Jin, Yi; Chen, Mo; Winkler, Jeffrey D; Penning, Trevor M

Published In J Med Chem, (2012 Mar 08)

Abstract: Aldo-keto reductase 1C3 (AKR1C3; type 5 17β-hydroxysteroid dehydrogenase) is overexpressed in castration resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5α-dihydrotestosterone. Selective AKR1C3 inhibitors are required because compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of 5α-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular, are potent but nonselective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid, as lead compound, five classes of structural analogues were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure-activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads toward new therapeutics for CRPC.

PubMed ID: 22263837 Exiting the NIEHS site

MeSH Terms: 20-Hydroxysteroid Dehydrogenases/antagonists & inhibitors; 3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors*; 3-Hydroxysteroid Dehydrogenases/genetics; 3-Hydroxysteroid Dehydrogenases/metabolism; Aldo-Keto Reductase Family 1 Member C3; Antineoplastic Agents/chemical synthesis*; Antineoplastic Agents/chemistry; Antineoplastic Agents/pharmacology; Cell Line, Tumor; Cyclooxygenase 1/metabolism; Cyclooxygenase 2/metabolism; Cyclooxygenase Inhibitors/chemical synthesis; Cyclooxygenase Inhibitors/chemistry; Cyclooxygenase Inhibitors/pharmacology; Fenamates/chemical synthesis*; Fenamates/chemistry; Fenamates/pharmacology; Humans; Hydroxyprostaglandin Dehydrogenases/antagonists & inhibitors*; Hydroxyprostaglandin Dehydrogenases/genetics; Hydroxyprostaglandin Dehydrogenases/metabolism; Hydroxysteroid Dehydrogenases/antagonists & inhibitors; Isoenzymes/antagonists & inhibitors; Male; Prostatic Neoplasms/drug therapy; Structure-Activity Relationship; Testosterone/antagonists & inhibitors; Testosterone/biosynthesis

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