Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists.
The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.
Xu
Yanping
Y
Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. xu_yanping@lilly.com
Rito
Christopher J
CJ
Etgen
Garret J
GJ
Ardecky
Robert J
RJ
Bean
James S
JS
Bensch
William R
WR
Bosley
Jacob R
JR
Broderick
Carol L
CL
Brooks
Dawn A
DA
Dominianni
Samuel J
SJ
Hahn
Patric J
PJ
Liu
Sha
S
Mais
Dale E
DE
Montrose-Rafizadeh
Chahrzad
C
Ogilvie
Kathy M
KM
Oldham
Brian A
BA
Peters
Mary
M
Rungta
Deepa K
DK
Shuker
Anthony J
AJ
Stephenson
Gregory A
GA
Tripp
Allie E
AE
Wilson
Sarah B
SB
Winneroski
Leonard L
LL
Zink
Richard
R
Kauffman
Raymond F
RF
McCarthy
James R
JR
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists*
C486784:2-methyl-3-(4-(2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy)phenyl)-2-phenoxypropionic acid; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D010666:Phenylpropionates; D018160:Receptors, Cytoplasmic and Nuclear; D013876:Thiophenes; D014157:Transcription Factors