Document Detail

Synthesis and evaluation of novel alpha-heteroaryl-phenylpropanoic acid derivatives as PPARalpha/gamma dual agonists.
MedLine Citation:
PMID:  19783444     Owner:  NLM     Status:  MEDLINE    
The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the alpha-position and their evaluation for binding and activation of PPARalpha and PPARgamma are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARalpha/gamma dual agonist (EC(50)=0.013 and 0.061 microM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.
Agustin Casimiro-Garcia; Christopher F Bigge; Jo Ann Davis; Teresa Padalino; James Pulaski; Jeffrey F Ohren; Patrick McConnell; Christopher D Kane; Lori J Royer; Kimberly A Stevens; Bruce Auerbach; Wendy Collard; Christine McGregor; Kun Song
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-09-06
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  17     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-10-06     Completed Date:  2010-01-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  7113-25     Citation Subset:  IM    
Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Rd, Ann Arbor, MI 48105, USA.
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MeSH Terms
Biological Availability
Blood Glucose / analysis
Crystallography, X-Ray
Drug Evaluation, Preclinical
Insulin / blood
Magnetic Resonance Spectroscopy
Mass Spectrometry
Mice, Transgenic
PPAR alpha / agonists*
PPAR gamma / agonists*
Propionic Acids / chemical synthesis*,  pharmacokinetics,  pharmacology*
Triglycerides / blood
Reg. No./Substance:
0/Blood Glucose; 0/PPAR alpha; 0/PPAR gamma; 0/Propionic Acids; 0/Triglycerides; 11061-68-0/Insulin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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