Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor delta agonists.

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Epple R, Cow C, Xie Y, Azimioara M, Russo R, Wang X, Wityak J, Karanewsky DS, Tuntland T, Nguyen-Tran VT, Cuc Ngo C, Huang D, Saez E, Spalding T, Gerken A, Iskandar M, Seidel HM, Tian SS

Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor delta agonists.

J Med Chem. 2010 Jan 14;53(1):77-105. doi: 10.1021/jm9007399.

PubMed ID

19928766 [ View in PubMed

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Abstract

The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor delta (PPARdelta) agonists are reported. The synthesis and structure-activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARdelta activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARdelta in skeletal muscle.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Cardarine	Peroxisome proliferator-activated receptor delta	EC 50 (nM)	5	N/A	N/A	Details
Cardarine	Peroxisome proliferator-activated receptor delta	EC 50 (nM)	6	N/A	N/A	Details