Novel Pirinixic Acids as PPARα Preferential Dual PPARα/γ Agonists

Abstract

Pirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that a-alkyl substitution leads to balanced low micromolar-active dual agonists of PPARa and PPARg. Taking a-hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3-dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPARg activity but further increased PPARa activity leading to nanomolar activities. Supporting docking studies proposed that the (R)-enantiomer should fit the PPARa ligand-binding pocket better and thus be more active than the (S)-enantiomer. Single enantiomers of selected active analogues were then prepared by enantio-selective synthesis and enantioselective preparative HPLC, respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation.

Tertiary Alkylamines as Nucleophiles in Substitution Reactions at Heteroaromatic Halide During the Synthesis of the Highly Potent Pirinixic Acid Derivative 2-(4-Chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic Acid (YS-121)

“…One of those byproducts was formed in high amounts in step (iii a). It was not described in former publications concerning that type of reaction [ 6 , 8 , 10 , 11 , 12 , 13 , 14 ], also with different aromatic amines as nucleophiles, and this forced us to modify the reaction procedure as well as the way of purification. In step (iii a) the chlorinated pyrimidine derivative 5 should be monoaminated to 6 by a nucleophilic aromatic substitution with 2,3-dimethylaniline.…”

Structural Insight Into the Crucial Role of Ligand Chirality in the Activation of PPARs by Crystallographic Methods

“…Notably, PPAR activation was merely affected. A very potent PPAR agonist with excellent selectivity over PPAR (107) was obtained by replacing the central pyrimidine ring of 105 by benzene and the amine linker by a larger propane-1,3-diol moiety [124][125][126].…”

Functionalization of Fatty Acid Mimetics for Solid‐Phase Coupling and Subsequent Target Identification

“…Notably, the substitution pattern of the biphenyl moiety had only minor impact on the PPAR activation and the dual mPGES‐1/5‐LO inhibition. PA derivative 1 is a PPARα/γ dual agonist with an EC 50 value of 0.19 µM for PPARα and 1.5 µM for PPARγ 1. Furthermore, this compound also shows high inhibitory activities for 5‐LO (IC 50 = 0.41 µM) and mPGES‐1 (IC 50 = 1.7 µM).…”

“…1) display an interesting pharmacophore with multiple biological activities. Previously, we have shown that pirinixic acid derivatives act as activators of a subclass of nuclear receptors i.e ., peroxisome proliferator‐activated receptors (PPARs) α and γ 1–3, and as inhibitors of distinct enzymes of the arachidonic acid cascade i.e ., microsomal prostaglandin E 2 ‐synthase‐1 (mPGES‐1) and 5‐lipoxygenase (5‐LO) 4, 5. PPAR agonists are widely used drugs in the treatment of the metabolic diseases dyslipidemia (PPARα agonists like fenofibrate) and type‐2 diabetes mellitus (PPARγ agonists like pioglitazone).…”

“…As a result, most active compounds for PPAR and mPGES‐1/5‐LO such as 1 (Fig. 2) contain an n ‐hexyl chain in the α‐position and a biphenyl residue coupled to the pyrimidine ring 1. Notably, the substitution pattern of the biphenyl moiety had only minor impact on the PPAR activation and the dual mPGES‐1/5‐LO inhibition.…”