4-(Anilino)pyrrole-2-carboxamides: Novel non-steroidal/non-anilide type androgen antagonists effective upon human prostate tumor LNCaP cells with mutated nuclear androgen receptor.
Various 4-(anilino)pyrrole-2-carboxamides were designed and synthesized as novel androgen receptor (AR) antagonists without steroidal or anilide structure, based on our strategy for developing full antagonists of nuclear receptors. Introduction of a bulky N-alkyl group, such as a cyclohexylmethyl or benzyl group, increased the binding affinity for wild-type AR and the potency for growth inhibition of androgen-dependent SC-3 cells. Among the compounds obtained, N-[4-[(benzyl)(4-nitrophenyl)amino]-1-methylpyrrole-2-carbonyl]pyrrolidine (22) is as potent an AR antagonist as the typical anilide-type AR antagonists hydroxyflutamide and bicalutamide. Further, compound 22 had potent binding affinity for T877A mutated AR, and dose-dependently inhibited the testosterone-induced production of prostate-specific antigen in LNCaP cells bearing T877A AR.
Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Ken-ichi
K
Wakabayashi
Keisuke
K
Imai
Hiroyuki
H
Miyachi
Yuichi
Y
Hashimoto
Aya
A
Tanatani
D000726:Androgen Antagonists / Q000737:chemistry* / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D009154:Mutation; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011485:Protein Binding / Q000235:genetics; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics*
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D011758:Pyrroles; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen