Discovery of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl) carbonyl]piperidin-4-yl}propan-2-ol: A novel, potent and selective type 5 17β-hydroxysteroid dehydrogenase inhibitor

Type 5 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD5), also known as aldo-keto reductase 1C3 (AKR1C3), is a member of the aldo-keto reductase superfamily of enzymes and is expressed in the human prostate. One of the main functions of 17 beta-HSD5 is to catalyze the conversion of the weak androgen, androstenedione, to the potent androgen, testosterone. The concentration of intraprostatic 5 alpha-dihydrotestosterone (DHT) in patients following chemical or surgical castration has been reported to remain as high as 39% of that of healthy men, with 17 beta-HSD5 shown to be involved in this androgen synthesis. Inhibition of 17 beta-HSD5 therefore represents a promising target for the treatment of castration-resistant prostate cancer (CRPC). To investigate this, we conducted high-throughput screening (FITS) and identified compound 2, which displayed a structure distinct from known 17 beta-HSD5 inhibitors. To optimize the inhibitory activity of compound 2, we first introduced a primary alcohol group. We then converted the primary alcohol group to a tertiary alcohol, which further enhanced the inhibitory activity, improved metabolic stability, and led to the identification of compound 17. Oral administration of compound 17 to castrated nude mice bearing the CWR22R xenograft resulted in the suppression of androstenedione (AD)-induced intratumoral testosterone production. Compound 17 also demonstrated good isoform selectivity, minimal inhibitory activity against either CYP or hERG, and enhanced pharmacokinetic and physicochemical properties. (C) 2013 Elsevier Ltd. All rights reserved.