TY - JOUR
T1 - 4-(Anilino)pyrrole-2-carboxamides
T2 - Novel non-steroidal/non-anilide type androgen antagonists effective upon human prostate tumor LNCaP cells with mutated nuclear androgen receptor
AU - Wakabayashi, Ken ichi
AU - Imai, Keisuke
AU - Miyachi, Hiroyuki
AU - Hashimoto, Yuichi
AU - Tanatani, Aya
N1 - Funding Information:
This study was supported by Kato Memorial Bioscience Foundation, and Grants-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and the Japan Society for the Promotion of Science. K.W. acknowledges the support of the Japan Society for the Promotion of Science in the form of a Fellowship for Japanese Junior Scientists.
PY - 2008/7/15
Y1 - 2008/7/15
N2 - 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.
AB - 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.
KW - Androgen
KW - Antagonist
KW - Mutated receptor
KW - Pyrrole-2-carboxamide
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U2 - 10.1016/j.bmc.2008.05.063
DO - 10.1016/j.bmc.2008.05.063
M3 - Article
C2 - 18571420
AN - SCOPUS:47349122948
VL - 16
SP - 6799
EP - 6812
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 14
ER -