Identification of a subtype selective human PPARα agonist through parallel-array synthesis

• Published in: Bioorganic & medicinal chemistry letters Vol. 11; no. 9; pp. 1225 - 1227
• Main Authors: Brown, Peter J., Stuart, L.William, Hurley, Kevin P., Lewis, Michael C., Winegar, Deborah A., Wilson, Joan G., Wilkison, William O., Ittoop, Olivia R., Willson, Timothy M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 07.05.2001; Elsevier
• Subjects: Biological and medical sciences; General and cellular metabolism. Vitamins; Medical sciences; Pharmacology. Drug treatments; Agonist; Cyclohexane derivatives; Rat; Lipids; Selectivity; Peroxisome proliferator; Organic sulfide; Structure activity relation; Carboxylic acid; Ureas; Dyslipemia; Chemical synthesis; Biological receptor; Human; Rodentia; Benzene derivatives; Oral administration; Metabolic diseases; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Mouse; Animal; Affinity; Solid phase; Hamster; Antilipemic agent
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00188-3

Using solid-phase, parallel-array synthesis, a series of urea-substituted thioisobutyric acids was synthesized and assayed for activity on the human PPAR subtypes. GW7647 ( 3) was identified as a potent human PPARα agonist with ∼200-fold selectivity over PPARγ and PPARδ, and potent lipid-lowering activity in animal models of dyslipidemia. GW7647 ( 3) will be a valuable chemical tool for studying the biology of PPARα in human cells and animal models of disease. Using solid-phase, parallel-array synthesis, a series of urea-substituted thioisobutyric acids was synthesized. GW7647 ( 3) was identified as a potent, selective human PPARα agonist.