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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / chemistry*
  • Androgen Antagonists / pharmacology
  • Androgen Receptor Antagonists
  • Cell Line, Tumor
  • Humans
  • Male
  • Mutation*
  • Prostate-Specific Antigen / antagonists & inhibitors
  • Prostatic Neoplasms / drug therapy*
  • Protein Binding / genetics
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology
  • Receptors, Androgen / genetics*

Substances

  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Pyrroles
  • Receptors, Androgen
  • Prostate-Specific Antigen