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Published on: March 28, 2013
INT131: a selective modulator of PPAR gamma
Alykhan Motani1, Zhulun Wang, Jennifer Weiszmann
1Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Journal of Molecular Biology
|May 20, 2009
Summary
INT131, a novel PPAR gamma ligand, shows antidiabetic effects with fewer cardiovascular side effects than traditional drugs. This selective modulator offers a promising new therapeutic avenue for type 2 diabetes treatment.
Area of Science:
- Endocrinology and Metabolism
- Molecular Pharmacology
- Drug Discovery
Background:
- Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a key target for type 2 diabetes treatments.
- Thiazolidinediones, a class of PPAR gamma agonists, have limitations.
- INT131 is a novel, selective PPAR gamma ligand distinct from glitazone agonists.
Purpose of the Study:
- To characterize INT131 as a selective PPAR gamma ligand.
- To investigate INT131's distinct pharmacological profile and potential therapeutic benefits.
- To compare INT131's efficacy and safety profile against existing antidiabetic drugs.
Main Methods:
- In vitro biochemical and cell-based functional assays.
- In vivo studies using Zucker (fa/fa) rats.
- X-ray crystallography and mutagenesis studies.
Main Results:
- INT131 demonstrated a unique pattern of coregulator recruitment and target gene activation in adipocytes.
- INT131 improved glucose tolerance in diabetic rats with a better adverse effect profile than rosiglitazone.
- X-ray crystallography revealed a distinct binding mode of INT131 to PPAR gamma.
Conclusions:
- INT131 selectively modulates PPAR gamma responses, offering antidiabetic efficacy with improved cardiovascular safety.
- INT131's unique binding mode and distinct pharmacology present a promising therapeutic strategy for type 2 diabetes.
- INT131 is under clinical evaluation for type 2 diabetes treatment.
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