Discovery of azetidinone acids as conformationally-constrained dual PPARalpha/gamma agonists.
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.
Wang
Wei
W
Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA.
Devasthale
Pratik
P
Farrelly
Dennis
D
Gu
Liqun
L
Harrity
Thomas
T
Cap
Michael
M
Chu
Cuixia
C
Kunselman
Lori
L
Morgan
Nathan
N
Ponticiello
Randy
R
Zebo
Rachel
R
Zhang
Litao
L
Locke
Kenneth
K
Lippy
Jonathan
J
O'Malley
Kevin
K
Hosagrahara
Vinayak
V
Zhang
Lisa
L
Kadiyala
Pathanjali
P
Chang
Chiehying
C
Muckelbauer
Jodi
J
Doweyko
Arthur M
AM
Zahler
Robert
R
Ryono
Denis
D
Hariharan
Narayanan
N
Cheng
Peter T W
PT
D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001682:Biological Availability; D003300:Copper / Q000494:pharmacology; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D050171:Dyslipidemias / Q000188:drug therapy; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
C116379:2-azetidinone; D001384:Azetidines; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D047493:PPAR alpha; D047495:PPAR gamma; D014280:Triglycerides; D003300:Copper; D005947:Glucose