title: Molecular determinants for improved activity at PPARα: structure-activity relationship of pirinixic acid derivatives, docking study and site-directed mutagenesis of PPARα.
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.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Lamers
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Dittrich
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Steri
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany. Electronic address: proschak@pharmchem.uni-frankfurt.de.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany. Electronic address: schubert-zsilavecz@pharmchem.uni-frankfurt.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047493:PPAR alpha; D011743:Pyrimidines; C006253:pirinixic acid
keywords: Dual PPARα/γ agonist; Metabolic syndrome; Peroxisome proliferator-activated receptor; Site-directed mutagenesis; Structure–activity relationship