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This Article Full Text Full Text (PDF) All Versions of this Article: 91/1/267S    most recent ajcn.2009.28449Ev1 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Higgins, L. S. Articles by DePaoli, A. M Search for Related Content PubMed PubMed Citation Articles by Higgins, L. S. Articles by DePaoli, A. M Agricola Articles by Higgins, L. S. Articles by DePaoli, A. M

Selective peroxisome proliferator-activated receptor (PPAR) modulation as a strategy for safer therapeutic PPAR activation^1,2,3

¹ From InteKrin Therapeutics Inc Los Altos CA.

² Presented at the symposium ‘‘Novel Therapeutic Advances through the Development of Selective PPAR Modulators from Bench to Bedside,’’ held at Experimental Biology 2009, New Orleans, LA, 21 April 2009.

³ Address correspondence and reprint requests to LS Higgins, InteKrin Therapeutics Inc, 4300 El Camino Real, Suite 201, Los Altos, CA 94022. E-mail: linda{at}intekrin.com.

Peroxisome proliferator-activated receptor (PPAR) is a clinically validated target for treatment of insulin resistance. PPAR activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPAR provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPAR is a nuclear receptor that forms a complex with coreceptor RXR and a cell type– and cell state–specific array of coregulators to control gene transcription. PPAR affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPAR modulator profile would include high-affinity interaction with the PPAR-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPAR modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy.

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