Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 6799-6812 |
| Number of pages | 14 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 16 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - Jul 15 2008 |
| Externally published | Yes |
Fingerprint
Keywords
- Androgen
- Antagonist
- Mutated receptor
- Pyrrole-2-carboxamide
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Organic Chemistry
- Drug Discovery
- Pharmaceutical Science
Cite this
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. / Wakabayashi, Ken ichi; Imai, Keisuke; Miyachi, Hiroyuki; Hashimoto, Yuichi; Tanatani, Aya.
In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 14, 15.07.2008, p. 6799-6812.Research output: Contribution to journal › Article
}
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
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
VL - 16
SP - 6799
EP - 6812
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 14
ER -