title: 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.
abstract: Type 5 17β-hydroxysteroid dehydrogenase (17β-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 17β-HSD5 is to catalyze the conversion of the weak androgen, androstenedione, to the potent androgen, testosterone. The concentration of intraprostatic 5α-dihydrotestosterone (DHT) in patients following chemical or surgical castration has been reported to remain as high as 39% of that of healthy men, with 17β-HSD5 shown to be involved in this androgen synthesis. Inhibition of 17β-HSD5 therefore represents a promising target for the treatment of castration-resistant prostate cancer (CRPC). To investigate this, we conducted high-throughput screening (HTS) and identified compound 2, which displayed a structure distinct from known 17β-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.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. kazushi.watanabe@astellas.com
authors.forename: Kazushi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Akio
authors.initials: A
authors.lastname: Kakefuda
authors.forename: Minoru
authors.initials: M
authors.lastname: Yasuda
authors.forename: Kentaro
authors.initials: K
authors.lastname: Enjo
authors.forename: Aya
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Furutani
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Naritomi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Otsuka
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C587054:2-methyl-1-(1-((5-methyl-1H-indol-2-yl)carbonyl)piperidin-4-yl)propan-2-ol; D004791:Enzyme Inhibitors; D007211:Indoles; D010880:Piperidines; D013739:Testosterone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3
keywords: Aldo-keto reductase 1C3 (AKR1C3); Castration-resistant prostate cancer (CRPC); Testosterone; Type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5)