title: In vitro and in vivo models for the evaluation of potent inhibitors of male rat 17alpha-hydroxylase/C17,20-lyase.
abstract: The C(17,20)-lyase is a key enzyme in the biosynthesis of androgens by both the testes and adrenals. A complete inhibition of this enzyme would provide an alternative means of androgen suppression for the treatment of prostatic cancers. In the present study, the inhibitory effects of new non-steroidal compounds were tested in vitro on rat C(17,20)-lyase versus abiraterone, a reference steroidal inhibitor. Their activities were also evaluated in vivo on plasma testosterone (T) and luteinizing hormone (LH) levels and on testes, adrenals, seminal vesicles (SV) and ventral prostate (VP) weights after 3 days of oral treatment to adult male rats (50mg/kg per day p.o.). Inhibition in the nanomolar range was obtained with TX 977, the lead racemate product in this series, and optimization is ongoing based on a slight dissociation observed between its two diastereoisomers, TX 1196-11 (S) and TX 1197-11 (R). These non-steroidal compounds (including YM 55208, a reference competitor) proved to be more active in vivo than abiraterone acetate in this model, but the observed impact on adrenal weight suggests that the specificity of lyase inhibition versus corticosteroid biosynthesis deserves further investigations with this new class of potentially useful agents for the treatment of androgen-dependent prostate cancer.
authors.affiliation: Preclinical R&D Department, Théramex, 6 Avenue Prince Héréditaire, Albert 98000, Monaco. iduc@theramex.mc
authors.forename: I
authors.initials: I
authors.lastname: Duc
authors.forename: P
authors.initials: P
authors.lastname: Bonnet
authors.forename: V
authors.initials: V
authors.lastname: Duranti
authors.forename: S
authors.initials: S
authors.lastname: Cardinali
authors.forename: A
authors.initials: A
authors.lastname: Rivière
authors.forename: A
authors.initials: A
authors.lastname: De Giovanni
authors.forename: J
authors.initials: J
authors.lastname: Shields-Botella
authors.forename: G
authors.initials: G
authors.lastname: Barcelo
authors.forename: N
authors.initials: N
authors.lastname: Adje
authors.forename: D
authors.initials: D
authors.lastname: Carniato
authors.forename: J
authors.initials: J
authors.lastname: Lafay
authors.forename: J C
authors.initials: JC
authors.lastname: Pascal
authors.forename: R
authors.initials: R
authors.lastname: Delansorne
mesh_terms: D000284:Administration, Oral; D000736:Androstenes; D000737:Androstenols / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013737:Testis / Q000201:enzymology; D013739:Testosterone / Q000097:blood
chemical_list: D000736:Androstenes; D000737:Androstenols; D004791:Enzyme Inhibitors; D013739:Testosterone; D007986:Luteinizing Hormone; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone