Design and synthesis of indane-ureido-thioisobutyric acids: A novel class of PPARα agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 24; pp. 6773 - 6778
• Main Authors: Matthews, Jay M., Chen, Xiaoli, Cryan, Ellen, Hlasta, Dennis J., Rybczynski, Philip J., Strauss, Kim, Tang, Yuting, Xu, June Z., Yang, Maria, Zhou, Lubing, Demarest, Keith T.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.12.2007; Elsevier
• Subjects: Aminoindane; Biological and medical sciences; Dyslipidemia; General and cellular metabolism. Vitamins; Hypoglycemic; Hypolipidemic; Medical sciences; Pharmacology. Drug treatments; PPARα agonist; Hypolipidemic; Aminoindane; Hypoglycemic; PPARα agonist; Dyslipidemia; Agonist; Nuclear receptor; Lipids; Organic sulfide; PPAR-α receptor; Hypoglycemic agent; Structure activity relation; Ureas; Dyslipemia; Chemical synthesis; Biological receptor; Indan derivatives; Rodentia; Oral administration; Metabolic diseases; Bioavailability; In vitro; In vivo; Vertebrata; Mammalia; Mouse; Animal; Fluorine Organic compounds; Pharmacokinetics; Antilipemic agent
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.10.041

The synthesis and SAR of novel, highly potent PPARα agonists based on an indane scaffold are reported. A series of aminoindane derivatives were synthesized and shown to be potent PPARα agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARα activation and PPARα mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague–Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/ db mice.