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International Journal of PharmTech Research

CODEN (USA): IJPRIF Vol.2, No.2, pp 1376-1382,

ISSN : 0974-4304 April-June 2010

Quantitative Structure Activity Relationship Studies of A Novel Class of Dual PPAR γ/δ Agonists

Mukesh Chandra Sharma*, Smita Sharma1

  • *

    School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshshila Campus, Khandwa Road,

Indore- 452 001 M.P, India 1Department of Chemistry Yadhunath Mahavidyalya Bhind- 477001 M.P, India *Corres. Author: mukeshcsharma@yahoo.com

ABSTRACT: The Peroxisome proliferators-activated receptors (PPARs) constitute a highly conserved set of ligand activated transcription factors in the nuclear hormone receptor subfamily. Selective modulation of PPAR could provide significant anti-diabetic activity with the reduction or elimination of side effects. These have increasingly become attractive targets for developing novel anti-type 2 diabetic drugs. In the present study the QSAR analysis was performed employing V-life MDS-3.0 software to retrieve information about structure activity relationships of some 3-{4-[3-(2- aryl-phenoxy)butoxy]-phenyl}propionic acids as novel PPAR γ/δ agonists. 2D QSAR methods were developed using Partial Least Square (PLS) and variable selection methods. Out of the 10 models developed, the two best 2D QSAR models having highest correlation coefficient and cross validated squared correlation coefficient were selected for further study, which are r2 = 0.9581, q2 = 0.9262, F test = 160.2108, pred_r2 = 0.3840, pred_r2se = 0.6413 and r2 = 0.9440, q2 = 0.8987, F test = 118.1064, pred_r2 = 0.5371, pred_r2se = 0.5559. 3D QSAR models were developed using kNN-MFA method, combined with simulated annealing selection procedure. Out of the 10 models developed the best 3D QSAR model having highest cross validated squared correlation coefficient was selected for further study, record as q2 = 0.8184, Pred_r2 = 0.7455.

KEY WORDS: 2D QSAR, PLS Regression, DUAL PPAR γ/δ, Diabetes.

2 INTRODUCTION Non-insulin dependent diabetes mellitus (NIDDM) is a major cause of mortality and morbidity in the population of industrialized world. It is a complex, chronic metabolic disorder characterized by insulin resistance in the liver and peripheral tissues and dysfunction of beta -cells1. Due to change in dietary habits and sedentary life style , it becomes a major concern both in developed as well as developing countries. Insulin resistance is considered to be the underlying mechanism in the pathogenesis of type 2 diabetes, which, if untreated, leads to dyslipidemia, hypertension and obesity, collectively known as metabolic syndrome 3. Untreated diabetes leads to severe macro and microvascular complications4.Type 2 diabetes is a metabolic disorder characterized by hyperglycemia and/or insulin resistance. It is often associated with obesity, hypertension and dyslipidemia. Current therapies for reducing plasma

glucose include the use of sulfonylureas, metformin, acarbose and thiazolidinones (TZDs). Statins and fibrate drugs act due to the activation of the peroxisome proliferators activated receptors (PPARs) γ and δ respectively. The PPARs constitute a highly conserved set of ligand activated transcription factors in the nuclear hormone receptor subfamily. Three distinct PPAR subtypes have been identified in most mammalian species each forming a functional heterodimer complex with 9 cis retinoic acid receptor (RXR). A series of compounds of 3-{4-[3-(2-aryl- phenoxy) butoxy]-phenyl} propionic acids was selected as novel PPAR γ/δ agonists for QSAR studies5.The peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily of ligand-modulated transcription factors. There are three PPAR subtypes, namely PPAR γ, δ and ß. PPAR γ play a central role in regulating the storage and catabolism of dietary fats.6 PPAR γ agonists, such as fenofibrate, are effective at lowering serum triglycerides and raising high-density lipoprotein

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