Discovery of azetidinone acids as conformationally-constrained dual PPARalpha/gamma agonists.

Abstract

A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

• Authors: Wei Wang, Pratik Devasthale, Dennis Farrelly, Liqun Gu, Thomas Harrity, Michael Cap, Cuixia Chu, Lori Kunselman, Nathan Morgan, Randy Ponticiello, Rachel Zebo, Litao Zhang, Kenneth Locke, Jonathan Lippy, Kevin O'Malley, Vinayak Hosagrahara, Lisa Zhang, Pathanjali Kadiyala, Chiehying Chang, Jodi Muckelbauer, Arthur M Doweyko, Robert Zahler, Denis Ryono, Narayanan Hariharan, Peter T W Cheng
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 6 Pg. 1939-44 (Mar 15 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18291645 (Publication Type: Journal Article)

Chemical References

• 2-azetidinone
• Azetidines
• Cytochrome P-450 Enzyme Inhibitors
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• PPAR alpha
• PPAR gamma
• Triglycerides
• Copper
• Glucose

Topics

• Administration, Oral
• Animals
• Azetidines (chemical synthesis, chemistry, pharmacology)
• Biological Availability
• Copper (pharmacology)
• Crystallography, X-Ray
• Cytochrome P-450 Enzyme Inhibitors
• Diabetes Mellitus, Experimental (drug therapy)
• Dyslipidemias (drug therapy)
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels (metabolism)
• Glucose (metabolism)
• Mice
• Mice, Mutant Strains
• Molecular Structure
• PPAR alpha (agonists, metabolism)
• PPAR gamma (agonists, metabolism)
• Protein Conformation
• Stereoisomerism
• Structure-Activity Relationship
• Triglycerides (blood)