ys-121 and pirinixic-acid

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.

Topics: Arachidonate 5-Lipoxygenase; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Intramolecular Oxidoreductases; Models, Molecular; Molecular Structure; PPAR alpha; PPAR gamma; Prostaglandin-E Synthases; Pyrimidines; Structure-Activity Relationship; Thiazoles

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.

Topics: Dose-Response Relationship, Drug; Humans; Hydrogen Bonding; Molecular Docking Simulation; Molecular Structure; Mutagenesis, Site-Directed; PPAR alpha; Pyrimidines; Structure-Activity Relationship

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.

Topics: Animals; Arachidonate 5-Lipoxygenase; Binding Sites; Drug Design; Humans; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Intramolecular Oxidoreductases; Lipoxygenase Inhibitors; Male; Mice; Microsomes; Models, Molecular; Peritonitis; Prostaglandin-E Synthases; Protein Conformation; Pyrimidines; Structure-Activity Relationship; Thiazoles; Zymosan

YS-121 [2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid] is the result of target-oriented structural derivatization of pirinixic acid. It is a potent dual PPARα/γ-agonist, as well as a potent dual 5-LO/mPGES-1-inhibitor. Additionally, recent studies showed an anti-inflammatory efficacy in vivo. Because of its interference with many targets, YS-121 is a promising drug candidate for the treatment of inflammatory diseases. Ongoing preclinical studies will thus necessitate huge amounts of YS-121. To cope with those requirements, we have optimized the synthesis of YS-121. Surprisingly, we isolated and characterized byproducts during the resulting from nucleophilic aromatic substitution reactions by different tertiary alkylamines at a heteroaromatic halide. These amines should actually serve as assisting bases, because of their low nucleophilicity. This astonishing fact was not described in former publications concerning that type of reaction and, therefore, might be useful for further reaction improvement in general. Furthermore, we could develop a proposal for the mechanism of that byproduct formation.

Topics: Amines; Hydrocarbons, Halogenated; Models, Chemical; Pyrimidines

Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in glucose and lipid homeostasis. PPARgamma agonists are in clinical use for the treatment of type 2 diabetes. Lately, a new class of selective PPARgamma modulators (SPPARgammaMs) was developed, which are believed to show less side effects than full PPARgamma agonists. We have previously shown that alpha-substitution of pirinixic acid, a moderate agonist of PPARalpha and PPARgamma, leads to low micromolar active balanced dual agonists of PPARalpha and PPARgamma. Herein we present modifications of pirinixic acid leading to subtype-selective PPARgamma agonists and furthermore the development of a selective PPARgamma modulator guided by molecular docking studies.

Topics: Drug Design; Models, Molecular; PPAR gamma; Pyrimidines

Dual inhibition of the prostaglandin (PG) and leukotriene (LT) biosynthetic pathway is supposed to be superior over single interference, both in terms of efficacy and side effects. Here, we present a novel class of dual microsomal PGE(2) synthase-1/5-lipoxygenase (5-LO) inhibitors based on the structure of pirinixic acid [PA, 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)acetic acid, compound 1]. Target-oriented structural modification of 1, particularly alpha substitution with extended n-alkyl or bulky aryl substituents and concomitant replacement of the 2,3-dimethylaniline by a biphenyl-4-yl-methane-amino residue, resulted in potent suppression of mPGES-1 and 5-LO activity, exemplified by 2-(4-(biphenyl-4-ylmethylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (7b, IC(50) = 1.3 and 1 microM, respectively). Select compounds also potently reduced PGE(2) and 5-LO product formation in intact cells. Importantly, inhibition of cyclooxygenases-1/2 was significantly less pronounced. Taken together, these pirinixic acid derivatives constitute a novel class of dual mPGES-1/5-LO inhibitors with a promising pharmacological profile and a potential for therapeutic use.

Topics: Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Cyclooxygenase 1; Cyclooxygenase 2; Drug Design; Enzyme Activation; Enzyme Inhibitors; Humans; Inflammation; Inhibitory Concentration 50; Intramolecular Oxidoreductases; Lipoxygenase Inhibitors; Models, Chemical; Prostaglandin-E Synthases; Pyrimidines

A novel class of potent 5-lipoxygenase (5-LO) product synthesis inhibitors based on the structure of pirinixic acid (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid, compound 1) is presented. Systematic profiling of 1, i.e., esterification of the carboxylic acid, alpha-substitution, and replacement of the o-dimethylaniline by 6-aminoquinoline, leads to potent suppressors of 5-LO product formation in activated polymorphonuclear leukocytes, exemplified by ethyl 2-[4-chloro-6-(quinoline-6-ylamino)-pyrimidin-2-ylsulfanyl]octane-1-carboxylate (6d, IC50 = 0.6 microM). These derivatives may possess potential for intervention with inflammatory and allergic diseases.

Topics: Aminoquinolines; Cells, Cultured; Esterification; Humans; Hypersensitivity; Inflammation; Leukocytes; Lipoxygenase; Lipoxygenase Inhibitors; Pyrimidines; Structure-Activity Relationship