Smithkline Beecham Corporation

Michael Vance Milburn

Millard Hurst Lambert, Iii

Barry George Shearer

Jeffrey Edmond Cobb

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 &mdash;CH OCH and wherein in Formula (II) X is C or N; and R is methyl, ethyl, n-propyl, i-propyl, &mdash;CH OCH , or &mdash;CO CH .

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Morrisville, NC, United States of America

Michael Vance Milburn