2-Alkoxydihydrocinnamates as PPAR agonists. Activity modulation by the incorporation of phenoxy substituents.
Herein we describe a series of potent and selective PPARgamma agonists with moderate PPARalpha affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.
Martín
José A
JA
Lilly Research Laboratories, Division of Eli Lilly & Company, Lilly S.A., Alcobendas 28108, Madrid, Spain. martin_jose_alfredo@lilly.com
Brooks
Dawn A
DA
Prieto
Lourdes
L
González
Rosario
R
Torrado
Alicia
A
Rojo
Isabel
I
López de Uralde
Beatriz
B
Lamas
Carlos
C
Ferritto
Rafael
R
Dolores Martín-Ortega
María
M
Agejas
Javier
J
Parra
Francisco
F
Rizzo
John R
JR
Rhodes
Gary A
GA
Robey
Roger L
RL
Alt
Charles A
CA
Wendel
Samuel R
SR
Zhang
Tony Y
TY
Reifel-Miller
Anne
A
Montrose-Rafizadeh
Chahrzad
C
Brozinick
Joseph T
JT
Hawkins
Eric
E
Misener
Elizabeth A
EA
Briere
Daniel A
DA
Ardecky
Robert
R
Fraser
James D
JD
Warshawsky
Alan M
AM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002934:Cinnamates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D051381:Rats; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D002934:Cinnamates; D047492:Peroxisome Proliferator-Activated Receptors; D014280:Triglycerides; C029010:cinnamic acid