Design and synthesis of dual peroxisome proliferator-activated receptors gamma and delta agonists as novel euglycemic agents with a reduced weight gain profile.
The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.
Xu
Yanping
Y
Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. xu_yanping@lilly.com
Etgen
Garret J
GJ
Broderick
Carol L
CL
Canada
Emily
E
Gonzalez
Isabel
I
Lamar
Jason
J
Montrose-Rafizadeh
Chahrzad
C
Oldham
Brian A
BA
Osborne
John J
JJ
Xie
Chaoyu
C
Shi
Qing
Q
Winneroski
Leonard L
LL
York
Jeremy
J
Yumibe
Nathan
N
Zink
Richard
R
Mantlo
Nathan
N
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D050171:Dyslipidemias / Q000188:drug therapy; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D047493:PPAR alpha / Q000235:genetics; D047494:PPAR delta / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013237:Stereoisomerism; D015533:Transcriptional Activation; D015430:Weight Gain / Q000187:drug effects*
C514167:3-(4-(3-(4-chloro-2-phenoxyphenoxy)butoxy)-2-ethylphenyl)propionic acid; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D010647:Phenyl Ethers; D010666:Phenylpropionates