ERRα is known to modulate transcription of genes critical in lipid metabolism making it an attractive target in the treatment of diabetes. Alkylidenyl diaryl ethers identified from high-throughput screening were subject to extensive SAR studies which led to the identification of an arylmethylenethiazolidinedione covalent inverse agonist of ERRα. The methylenethiazolidinedione moiety of the inverse agonist reacted with the sulfhydryl group of cysteine Cys325 in the binding pocket of ERRα. The other components of the agonist played a critical role by engaging in favorable noncovalent interactions with residues within the pocket. Pharmacokinetic studies indicated a very slowly reversible covalent interaction between inverse agonist and EERα with a half-life of ~18 h. Additionally, the identified covalent inverse agonist showed little to no off-target activity. In vivo studies indicated that the identified covalent inverse agonist improved glucose tolerance exhibiting potential as development of treatment for type 2 diabetes. 285