Development of Potent
and Selective Inhibitors of Aldo–Keto Reductase 1C3 (Type 5
17β-Hydroxysteroid Dehydrogenase) Based on <i>N</i>-Phenyl-Aminobenzoates and Their Structure–Activity Relationships
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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, <i>N</i>-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 <i>meta</i>-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