Synthesis and structure - Activity relationship studies of novel dihydropyridones as androgen receptor modulators

Antonella Pepe, Michae Pamment, Yeong Sang Kim, Sunmin Lee, Min Jung Lee, Kristin Beebe, Anton Filikov, Len Neckers, Jane B. Trepel, Sanjay V. Malhotra

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

A library of 3-hydroxy-2,3-dihydropyridones was synthesized, and their activities as antiandrogens were tested in the human prostate cancer cell line LNCaP. Structure-activity relationship (SAR) studies resulted in the identification of a potent compound whose activity is comparable to that of MDV3100. Homology modeling and molecular mechanics were used to build a structural model of the androgen receptor-ligand binding domain and to investigate the structural basis of the antagonism. The model is qualitatively consistent with the observed SAR. Moreover, the enrichment plot shows that screening with the model performs significantly better than random screening. Therefore, the model probably represents a realistic conformation of the antagonist form and can be utilized for structure-based design of novel antiandrogens.

Original languageEnglish (US)
Pages (from-to)8280-8297
Number of pages18
JournalJournal of Medicinal Chemistry
Volume56
Issue number21
DOIs
StatePublished - Nov 14 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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