title: 4-Methyl-3-oxo-4-aza-5alpha-androst-1-ene-17beta-N-aryl-carboxamides: an approach to combined androgen blockade [5alpha-reductase inhibition with androgen receptor binding in vitro].
abstract: 4-Aza-5alpha-androstan-3-one 17beta-(N-substituted carboxamides) are potent human type 2 5alpha-reductase (5aR) inhibitors with generally poor binding to the human androgen receptor (hAR). When the 17-amide N-substituent included an aromatic residue, potent dual inhibitors of both type 1 and 2 5aR are produced, but hAR binding remained poor. Tertiary-substituted-17-amides have reduced inhibition of both 5aR isozymes. The addition of an N4-methyl substitutent to the A-ring profoundly increased hAR affinity and the addition of unsaturation to the A-ring (delta1) modestly augmented hAR binding. The unsubstituted carbanilides in the delta1-N4-methyl series show some selectivity for type 1 5aR over the type 2 isozyme, whereas addition of aryl substituents, particularly at the 2-position, increased type 2 5aR binding to provide dual inhibitors with excellent hAR binding, e.g. N-(2-chlorophenyl)-3-oxo-4-methyl-4-aza-5alpha-androst-1-ene-17bet a-carboxamide (9c). Compounds of this type exhibit low nanomolar IC50s for both human 5aR isozymes as well as the human androgen receptor. Kinetic analysis confirms that the prototype 9c displays reversible, competitive inhibition of both human isozymes of 5aR with K(i) values of less than 10 nM. Furthermore, this compound binds to the androgen receptor with an IC50 equal to 8 nM. Compounds in this series are projected to be powerful antagonists of testosterone and dihydrotestosterone action in vivo, with potential utility in the treatment of prostatic carcinoma (PC).
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Tolman
authors.forename: S P
authors.initials: SP
authors.lastname: Sahoo
authors.forename: R K
authors.initials: RK
authors.lastname: Bakshi
authors.forename: D
authors.initials: D
authors.lastname: Gratale
authors.forename: G
authors.initials: G
authors.lastname: Patel
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: J
authors.initials: J
authors.lastname: Toney
authors.forename: B
authors.initials: B
authors.lastname: Chang
authors.forename: G S
authors.initials: GS
authors.lastname: Harris
mesh_terms: D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D000736:Androstenes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001378:Azasteroids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D000736:Androstenes; D000970:Antineoplastic Agents; D001378:Azasteroids; D004791:Enzyme Inhibitors; D007527:Isoenzymes