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.

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Wakabayashi K, Imai K, Miyachi H, Hashimoto Y, Tanatani A

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.

Bioorg Med Chem. 2008 Jul 15;16(14):6799-812. doi: 10.1016/j.bmc.2008.05.063. Epub 2008 Jun 18.

PubMed ID

18571420 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(R)-Bicalutamide	Androgen receptor	Ki (nM)	3700	N/A	N/A	Details
(R)-Bicalutamide	Androgen receptor	IC 50 (nM)	270	N/A	N/A	Details
Flutamide	Androgen receptor	Ki (nM)	3700	N/A	N/A	Details
Flutamide	Androgen receptor	IC 50 (nM)	4200	N/A	N/A	Details