title: 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.
abstract: 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.
authors.affiliation: Metabolic Diseases Chemistry, Bristol-Myers Squibb R&D, PO Box 5400, Princeton, NJ 08543-5400, USA. xiang-yang.ye@bms.com
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Ye
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chen
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Locke
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Malley
authors.forename: Litao
authors.initials: L
authors.lastname: Zhang
authors.forename: Raijit
authors.initials: R
authors.lastname: Srivastava
authors.forename: Bowman
authors.initials: B
authors.lastname: Miao
authors.forename: Daniel
authors.initials: D
authors.lastname: Meyers
authors.forename: Hossain
authors.initials: H
authors.lastname: Monshizadegan
authors.forename: Debra
authors.initials: D
authors.lastname: Search
authors.forename: Denise
authors.initials: D
authors.lastname: Grimm
authors.forename: Rongan
authors.initials: R
authors.lastname: Zhang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lippy
authors.forename: Celeste
authors.initials: C
authors.lastname: Twamley
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Muckelbauer
authors.forename: Chiehying
authors.initials: C
authors.lastname: Chang
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.forename: Vinayak
authors.initials: V
authors.lastname: Hosagrahara
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.forename: T-J
authors.initials: TJ
authors.lastname: Yang
authors.forename: Ranjan
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Peter T W
authors.initials: PT
authors.lastname: Cheng
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Tino
mesh_terms: 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
chemical_list: D000893:Anti-Inflammatory Agents; D047493:PPAR alpha; D047495:PPAR gamma; D005998:Glycine