title: Aminothiazole-featured pirinixic acid derivatives as dual 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 inhibitors with improved potency and efficiency in vivo.
abstract: Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2-aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.4 μM, respectively) and bioactivity in vivo. Computational analysis presumes binding sites of 16 at the tip of the 5-LO catalytic domain and within a subpocket of the mPGES-1 active site. Compound 16 (10 μM) hardly suppressed cyclooxygenase (COX)-1/2 activities, failed to inhibit 12/15-LOs, and is devoid of radical scavenger properties. Finally, compound 16 reduced vascular permeability and inflammatory cell infiltration in a zymosan-induced mouse peritonitis model accompanied by impaired levels of cysteinyl-leukotrienes and prostaglandin E2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hanke
authors.forename: Friederike
authors.initials: F
authors.lastname: Dehm
authors.forename: Stefanie
authors.initials: S
authors.lastname: Liening
authors.forename: Sven-Desiderius
authors.initials: SD
authors.lastname: Popella
authors.forename: Jonas
authors.initials: J
authors.lastname: Maczewsky
authors.forename: Max
authors.initials: M
authors.lastname: Pillong
authors.forename: Jens
authors.initials: J
authors.lastname: Kunze
authors.forename: Christina
authors.initials: C
authors.lastname: Weinigel
authors.forename: Dagmar
authors.initials: D
authors.lastname: Barz
authors.forename: Astrid
authors.initials: A
authors.lastname: Kaiser
authors.forename: Mario
authors.initials: M
authors.lastname: Wurglics
authors.forename: Michael
authors.initials: M
authors.lastname: Lämmerhofer
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008861:Microsomes / Q000201:enzymology*; D008958:Models, Molecular; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy; D000071876:Prostaglandin-E Synthases; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*; D015054:Zymosan / Q000494:pharmacology
chemical_list: D016859:Lipoxygenase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C006253:pirinixic acid; D015054:Zymosan; D001094:Arachidonate 5-Lipoxygenase; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse