title: Synthesis and biological evaluation of novel pyrrolidine acid analogs as potent dual PPARα/γ agonists.
abstract: The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Hao
authors: H
authors: Zhang
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Charles Z
authors: CZ
authors: Ding
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Zhi
authors: Z
authors: Lai
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Sean S
authors: SS
authors: Chen
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Pratik
authors: P
authors: Devasthale
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Tim
authors: T
authors: Herpin
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: George
authors: G
authors: Morton
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Fucheng
authors: F
authors: Qu
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Denis
authors: D
authors: Ryono
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Rebecca
authors: R
authors: Smirk
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Wei
authors: W
authors: Wang
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Shung
authors: S
authors: Wu
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Xiang-Xang
authors: XX
authors: Ye
authors: Discovery Analytical Sciences, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Yi-Xin
authors: YX
authors: Li
authors: Discovery Analytical Sciences, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Atsu
authors: A
authors: Apedo
authors: Metabolic Diseases Biology, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Dennis
authors: D
authors: Farrelly
authors: Lead Evaluation, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Tao
authors: T
authors: Wang
authors: Metabolic Diseases Biology, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Liqun
authors: L
authors: Gu
authors: Metabolic Diseases Biology, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Nathan
authors: N
authors: Morgan
authors: Metabolic Diseases Biology, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Neil
authors: N
authors: Flynn
authors: Metabolic Diseases Biology, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Cuixia
authors: C
authors: Chu
authors: Metabolic Diseases Biology, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Lori
authors: L
authors: Kunselman
authors: Lead Evaluation, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Jonathan
authors: J
authors: Lippy
authors: Lead Evaluation, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Kenneth
authors: K
authors: Locke
authors: Lead Evaluation, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Kevin
authors: K
authors: O'Malley
authors: Metabolic Diseases Biology, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Thomas
authors: T
authors: Harrity
authors: Metabolic Diseases Biology, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Michael
authors: M
authors: Cap
authors: Metabolism and Pharmacokinetics, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Lisa
authors: L
authors: Zhang
authors: Metabolism and Pharmacokinetics, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Vinayak
authors: V
authors: Hosagrahara
authors: Metabolism and Pharmacokinetics, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Pathanjali
authors: P
authors: Kadiyala
authors: Metabolism and Pharmacokinetics, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Carrie
authors: C
authors: Xu
authors: Computer-Assisted Drug Design, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Arthur M
authors: AM
authors: Doweyko
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Robert
authors: R
authors: Zahler
authors: Metabolic Diseases Biology, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
authors: Narayanan
authors: N
authors: Hariharan
authors: Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
authors: Peter T W
authors: PT
authors: Cheng
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D005260:Female; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D008024:Ligands; D051379:Mice; D008820:Mice, Obese; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D011759:Pyrrolidines; D014280:Triglycerides; C032519:pyrrolidine
keywords: Dual agonists; Peroxisome Proliferator-Activated Receptor; Pyrrolidine acid; Type 2 diabetes