INT131: A Selective Modulator of PPARγ

May 20, 2009Journal of molecular biology

INT131: a drug that selectively adjusts PPAR gamma activity

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Abstract

INT131 has been shown to improve glucose tolerance in Zucker (fa/fa) rats after 14 days of oral treatment.

INT131 is a selective ligand for the nuclear hormone receptor PPAR gamma, distinguished from traditional thiazolidinediones.
In adipocyte studies, INT131 induced minimal differentiation while partially activating specific PPAR gamma target genes related to adipogenesis.
INT131 exhibited more agonistic activity on target genes that may directly influence insulin sensitivity.
Compared to rosiglitazone, INT131 displayed similar improvements in glucose tolerance but less impact on heart and lung weights and overall weight gain.
X-ray crystallography indicated that INT131 binds to PPAR gamma through a unique mechanism, primarily involving hydrophobic interactions.
Mutagenesis studies suggest that the residue Tyr473 in helix 12 is crucial for activation by rosiglitazone but not for INT131, highlighting its distinct pharmacological profile.

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The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma; NR1C3) plays a central role in adipogenesis and is the molecular target of the thiazolidinedione class of antidiabetic drugs. To overcome the well-known shortcomings of thiazolidinediones, we have identified INT131 (formerly T131 and AMG131) as a potent selective ligand for PPAR gamma that is structurally and pharmacologically distinct from glitazone agonists. In vitro biochemical and cell-based functional assays showed that INT131 mediates a distinct pattern of coregulator recruitment to PPAR gamma. In adipocytes, INT131 showed minimal stimulation of adipocyte differentiation and partially activated PPAR gamma target genes involved in adipogenesis and, at the same time, showed more agonistic activity on another set of target genes that may influence insulin sensitivity directly. These unique properties of INT131 may provide a mechanistic basis for its distinct pharmacological profile. In vivo, increases in glucose tolerance were observed in Zucker (fa/fa) rats following a 14-day oral treatment with INT131. Although the maximal efficacies of INT131 and rosiglitazone were similar with respect to improvements in glucose tolerance, INT131 had less effect on heart and lung weights, weight gain, hemodilution, and plasma volume. Thus, INT131 appears to selectively modulate PPAR gamma responses in an in vivo preclinical model, showing antidiabetic efficacy while exhibiting an improved hemodynamic and cardiovascular adverse effect profile compared to the full agonist rosiglitazone. X-ray crystallography revealed that INT131 interacts with PPAR gamma through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket without direct hydrogen-bonding interactions to key residues in helix 12 that are characteristic of full agonists. Mutagenesis studies on Tyr473 in helix 12 demonstrated this residue as essential for rosiglitazone-induced receptor activation, but nonessential for INT131 function in vitro, providing one possible molecular determinant for INT131's distinct pharmacology. INT131 is currently being evaluated in a clinical setting as a therapeutic agent for the treatment of type 2 diabetes.

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INT131: A Selective Modulator of PPARγ

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