Indanylacetic Acid Derivatives Carrying 4-Thiazolyl-phenoxy Tail Groups, a New Class of Potent PPAR α/γ/δ Pan Agonists:  Synthesis, Structure−Activity Relationship, and In Vivo Efficacy

Abstract

Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship (SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists. While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of PPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were not known in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivatives with potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was found to exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gamma activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while normalizing glucose levels in diabetic rodent models.

PPAR Modulators and PPAR Pan Agonists for Metabolic Diseases: The Next Generation of Drugs Targeting Peroxisome Proliferator-Activated Receptors?

“…6) [56,57]. The work focused on the optimization of the lipophilic tail in order to enhance PPAR pan agonist activity in addition to drug properties, most notably favorable pharmacokinetics.…”

In silico structure-based drug design approach to develop novel pharmacophore model of human peroxisome proliferator-activated receptor γ agonists

“…The exclusion constraint feature is an object that represents an excluded volume in space, within a given radius. The excluded volumes are placed on regions of space that are occupied by the inactive molecules but not In order to validate the hypothesis, the 3D coordinates of the agonist (EHA 201) interaction points were then used as a search query against the compound library comprising PPAR agonists (Rudolph et al, 2007;Oguchi et al, 2000). The conformational models for these PPAR agonists were generated within Catalyst using the following settings: Maximum number of conformers = 250, Generation type = best quality, Energy range = 20 kcal/mol above the calculated lowest energy conformation.…”

Common binding requirements of PPAR-α/δ/γ pan agonists: quantitative structure–activity relationship analysis of indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail group

“…The chemical structures of all the molecules of indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail groups (Rudolph et al, 2007) were sketched and their geometries were cleaned using stand-alone module of Discovery Studio (version 2.0) and were loaded via.mol files into the work sheet of TSAR. TSAR is an integrated analysis package for the interactive investigation of QSARs.…”

“…The molecules of the series (Table 1; Rudolph et al, 2007) were divided into training set and the test set. Training set was used to build linear models so that an accurate relationship could be found between structures and biological activity.…”