Molecular determinants for improved activity at PPARα: structure-activity relationship of pirinixic acid derivatives, docking study and site-directed mutagenesis of PPARα

  • Bioorg Med Chem Lett. 2014 Aug 15;24(16):4048-52. doi: 10.1016/j.bmcl.2014.05.058.
Christina Lamers  1 ,  Michaela Dittrich  1 ,  Ramona Steri  1 ,  Ewgenij Proschak  2 ,  Manfred Schubert-Zsilavecz  3
Affiliations
  • 1. Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
  • 2. Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany. Electronic address: [email protected].
  • 3. Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany. Electronic address: [email protected].
PMID: 25022880 DOI: 10.1016/j.bmcl.2014.05.058
Abstract

Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of the metabolic syndrome. Especially a combination of PPARα and PPARγ agonistic activity seems worthwhile to be pursued. Herein we present the design and synthesis of a series of pirinixic acid derivatives as potent PPARα particularly dual PPARα/γ agonists with 2-((4-chloro-6-((4-(phenylamino)phenyl)amino)pyrimidin-2-yl)thio)octanoicacid having the highest potential. Our investigations based on molecular docking and structure-activity relationship (SAR) studies elucidated structural determinants affecting the potency at PPARα. A diphenylamine-scaffold seems to play a key role. Careful in silico analysis revealed an essential role for a hydrogen bond between the diphenylamine and a water cluster. We confirmed this hypothesis using a mutated PPARα LBD in our transactivation assay to disrupt the water cluster and to validate the proposed interaction.

Keywords
Dual PPARα/γ agonist; Metabolic syndrome; Peroxisome proliferator-activated receptor; Site-directed mutagenesis; Structure–activity relationship.