title: In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3).
abstract: BACKGROUND
  Aldo-keto reductase 1C3 [AKR1C3;17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)], plays a crucial role in persistent production of androgens despite castration, by catalysing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol and testosterone (T). Hence, AKR1C3 is a promising therapeutic target in castration-resistant prostate cancer, as combination of an AKR1C3 inhibitor and a gonadotropin-releasing hormone analogue may lead to complete androgen blockade. This study describes the preclinical characterisation of the novel AKR1C3 inhibitor ASP9521.
  
  
  METHODS
  The inhibitory effect of ASP9521 on AKR1C3-mediated conversion from AD into T was evaluated both in vitro and in vivo, using CWR22R xenografted mice. The effect of ASP9521 on PSA production and cell proliferation was tested using LNCaP cells stably expressing human AKR1C3 (LNCaP-AKR1C3). Pharmacokinetics of ASP9521 were studied in rats, dogs and cynomolgus monkeys.
  
  
  RESULTS
  ASP9521 inhibited conversion of AD into T by recombinant human or cynomolgus monkey AKR1C3 in a concentration-dependent manner (IC50,human: 11 nmol/L; IC50,monkey: 49 nmol/L). ASP9521 showed >100-fold selectivity for AKR1C3 over the isoform AKR1C2. In LNCaP-AKR1C3 cells, ASP9521 suppressed AD-dependent PSA production and cell proliferation. In CWR22R xenografts, single oral administration of ASP9521 (3 mg/kg) inhibited AD-induced intratumoural T production and this inhibitory effect was maintained for 24 h. After oral administration, ASP9521 was rapidly eliminated from plasma, while its intratumoural concentration remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) was 35 %, 78 % and 58 % in rats, dogs and monkeys, respectively.
  
  
  CONCLUSIONS
  ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor.
authors: Research Portfolio & Science Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors: Aya
authors: A
authors: Kikuchi
authors: Takashi
authors: T
authors: Furutani
authors: Hidenori
authors: H
authors: Azami
authors: Kazushi
authors: K
authors: Watanabe
authors: Tatsuya
authors: T
authors: Niimi
authors: Yoshiteru
authors: Y
authors: Kamiyama
authors: Sadao
authors: S
authors: Kuromitsu
authors: Edwina
authors: E
authors: Baskin-Bey
authors: Marten
authors: M
authors: Heeringa
authors: Taoufik
authors: T
authors: Ouatas
authors: Kentaro
authors: K
authors: Enjo
mesh_terms: D000284:Administration, Oral; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D004285:Dogs; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008807:Mice, Inbred BALB C; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism
chemical_list: C000598424:1-(1-((5-methoxy-1H-indol-2-yl)carbonyl)piperidin-4-yl)-2-methylpropan-2-ol; D004791:Enzyme Inhibitors; D007211:Indoles; D010880:Piperidines; D013739:Testosterone; D000735:Androstenedione; C510576:Akr1c6 protein, mouse; D004960:Estradiol Dehydrogenases