OXAZOLE PPAR ANTAGONISTS

A method is disclosed for rational design of a PPAR, FXR, LXR-alpha, or LXR-beta antagonist comprising chemical modification of a PPAR, FXR, LXR-alpha, or LXR-beta agonist to: a) prevent formation of a hydrogen bond between the agonist and tyrosine or histidine, or tryptophan involved in receptor activation; and/or b) displace the tyrosine or histidine, or tryptophan involved in receptor activation from its agonist bound position. Preferably, little or no additional changes are made in the structure of the agonist so that the resulting antagonist is a close structural analogue of the agonist. Specific examples of PPAR gamma antagonists designed and prepared using the method of this invention are compounds of Formula (I) or (II), or pharmaceutically acceptable salts or solvates thereof, where in Formula (I) X is O, S, or NH; and R is methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, phenyl, or -CH2OCH3 and wherein in Formula (II) X is C or N; and R is methyl, ethyl, n-propyl, i-propyl, -CH2OCH3, or -CO2CH3.