Type 5 17�-hydroxysteroid dehydrogenase (17�-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�-HSD5 is to catalyze the conversion of the weak androgen, androstenedione, to the potent androgen, testosterone. The concentration of intraprostatic 5a-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�-HSD5 shown to be involved in this androgen synthesis. Inhibition of 17�-HSD5 therefore represents a promising target for the treatment of castration-resistant prostate cancer (CRPC).We obtained a lead compound having a non-steroidal scaffold by high throughput screening (HTS) approaches for targeting enzyme activity of 17�-HSD5. After optimizations of the lead compound, we found ASP9521 as a potent, selective, and orally bioavailable 17�-HSD5 inhibitor.Oral administration of ASP9521 to castrated nude mice bearing the CWR22R xenograft resulted in the suppression of androstenedione-induced intratumoral testosterone production. ASP9521 also demonstrated good isoform selectivity, minimal inhibitory activity against either CYP or hERG, and preferable pharmacokinetic and physicochemical properties.

Discovery of ASP9521, a novel, potent, selective 17<i>�</i>-HSD5 inhibitor

246th National Meeting (2013)

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Discovery of ASP9521, a novel, potent, selective 17�-HSD5 inhibitor