Synthesis and structure-activity relationships of 2-aryl-4-oxazolylmethoxy benzylglycines and 2-aryl-4-thiazolylmethoxy benzylglycines as novel, potent PPARalpha selective activators- PPARalpha and PPARgamma selectivity modulation.
The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARalpha/gamma dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARalpha versus PPARgamma. Potent, highly selective PPARalpha activators 2a and 2l, as well as PPARalpha activators with significant PPARgamma activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.
Ye
Xiang-Yang
XY
Metabolic Diseases Chemistry, Bristol-Myers Squibb R&D, PO Box 5400, Princeton, NJ 08543-5400, USA. xiang-yang.ye@bms.com
Chen
Stephanie
S
Zhang
Hao
H
Locke
Kenneth T
KT
O'Malley
Kevin
K
Zhang
Litao
L
Srivastava
Raijit
R
Miao
Bowman
B
Meyers
Daniel
D
Monshizadegan
Hossain
H
Search
Debra
D
Grimm
Denise
D
Zhang
Rongan
R
Lippy
Jonathan
J
Twamley
Celeste
C
Muckelbauer
Jodi K
JK
Chang
Chiehying
C
An
Yongmi
Y
Hosagrahara
Vinayak
V
Zhang
Lisa
L
Yang
T-J
TJ
Mukherjee
Ranjan
R
Cheng
Peter T W
PT
Tino
Joseph A
JA
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001665:Binding Sites; D006224:Cricetinae; D018360:Crystallography, X-Ray; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D047493:PPAR alpha; D047495:PPAR gamma; D005998:Glycine