title: Identification of pirinixic acid derivatives bearing a 2-aminothiazole moiety combines dual PPARα/γ activation and dual 5-LO/mPGES-1 inhibition.
abstract: The concept of dual PPARα/γ activation was originally proposed as a new approach for the treatment of the metabolic syndrome. However, recent results indicated that PPARα as well as PPARγ activation might also be beneficial in the treatment of inflammatory diseases and cancer. We have recently identified aminothiazole-featured pirinixic acids as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors. Here we present the structure-activity relationship of these aminothiazole-featured pirinixic acids as dual PPARα/γ agonists and discuss their advantages with their potential as dual 5-LO/mPGES-1 inhibitors in inflammatory and cancer diseases. Various pirinixic acid derivatives had already been identified as dual PPARα/γ agonists. However, within this series of aminothiazole-featured pirinixic acids we were able to identify the most potent selective PPARγ agonistic pirinixic acid derivative (compound 13, (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid)). Therefore, docking of 13 on PPARγ was performed to determine the potential binding mode.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hanke
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; ETH Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland.
authors.forename: Roberto Carrasco
authors.initials: RC
authors.lastname: Gomez
authors.affiliation: ETH Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland.
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
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: D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D047493:PPAR alpha; D047495:PPAR gamma; D011743:Pyrimidines; D013844:Thiazoles; C004483:2-aminothiazole; C006253:pirinixic acid; D001094:Arachidonate 5-Lipoxygenase; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
keywords: 5-LO; Cancer; Inflammation; PPARα; PPARγ; mPGES-1