title: 17-Imidazolyl, pyrazolyl, and isoxazolyl androstene derivatives. Novel steroidal inhibitors of human cytochrome C17,20-lyase (P450(17 alpha).
abstract: We recently described a number of inhibitors of P450(17 alpha), the key enzyme of androgen biosynthesis. Here, we report the synthesis and activity of novel 17-imidazolyl, pyrazolyl, and isoxazolyl androstene derivatives as potential agents for the treatment of prostatic cancer. A number of 17-(4'-Imidazolyl) derivatives were prepared by condensing the corresponding 17-ketol acetate side chain with aldehyde and ammonium hydroxide. The 17 beta-(4'imidazolyl) derivatives (2a, 2e, 4a, 4c) were found to be potent inhibitors of human testicular P450(17 alpha), with greater activity than ketoconazole. The juxtaposition between the imidazole ring and the steroid D ring appears to be important in contributing inhibitory properties, Compounds having a 17 beta-(2'-imidazolyl) ring (9a, 10) or a 20 beta-(2'-imidazolyl) ring (12), instead of the 17 beta-(4'-imidazolyl) ring (2a, 4a), are weak inhibitors. Among the 17-(4'-imidazolyl) derivatives, introduction of the 17 alpha-hydroxy group (4b) and 16 alpha,17 alpha-epoxide group (2d) diminished potency (2a-->2d; lC50 66-->430 nM; 4a-->4b; lC50 58-->1200 nM), while the 16,17 double bond increased the inhibitory activity by almost three times in the 5-en-3 beta-ol inhibitors (2a-->2e; lC50 60-->24 nM). There was virtually no difference in the inhibitory activity in the 4-en-3-one inhibitors (4a-->4c; IC50 58-->50 nM). The introduction of a methyl (2b) or phenyl group (2c) on the 2'-position of 4'-imidazolyl ring caused a dramatic decrease in the potency. As to modification of the A,B rings, the 3-acetate (2f, 2g) decreased the potency almost 3-fold compared with the 3-alcohol (2e-->2f, IC50 24-->75 nM; 2a-->2g, 66-->199 nM) and the conversion from the 5-en-3 beta-ol into the 4-en-3-one hardly affected the potency. As expected, 4c was more potent than 2e for the rat p450(17 alpha). 17-(3'Pyrazolyl)-(14b) and 17-(5'-isoxazolyl)-androsta-5,16-dien-3 beta-ol (15b) were also potent inhibitors of P450(17 alpha), whereas the 17-(2'-imidazolyl) compound (9b) was one of the most potent inhibitor in this series. However, their 16-saturated counterparts (9a, 14a, 15a) were weak inhibitors. The 17 beta-(3'-isoxazolyl)- (16) and 17 beta-(5'-methyl-3'-oxazolyl)androst-5-en-3 beta-ol (18) were also inactive. The introduction of a methyl of phenyl group on the nitrogen of the pyrazolyl ring of 14b [see 14c, 14d, and 14e] also caused some loss of inhibition for P450(17 alpha). Compounds 2e, 4a, 4c, 9b, 14d, 17a, and 17b are among the most potent inhibitors of human P450(17 alpha) so far reported.
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore 21201, USA.
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Ling
authors.forename: J S
authors.initials: JS
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.forename: G T
authors.initials: GT
authors.lastname: Klus
authors.forename: A
authors.initials: A
authors.lastname: Brodie
mesh_terms: D000736:Androstenes / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000201:enzymology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology
chemical_list: D000736:Androstenes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007555:Isoxazoles; D011720:Pyrazoles; D013254:Steroid 17-alpha-Hydroxylase