Synthesis and Identification of [1,2,4]thiadiazole Derivatives As a New Series of Potent and Orally Active Dual Agonists of Peroxisome Proliferator-activated Receptors Alpha and Delta.
From: Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Cedarbrook Corporate Center, 8 Clarke Drive, Cranbury, NJ 08512, USA.
Journal of medicinal chemistry
- Publish Date: Aug 2007
- ISSN: 0022-2623
- Volume: 50
- Issue: 16
- Pages: 3954-63
- Medium: Print
- Language: English
- Citation (JAMA): Shen Lan, Zhang Yan, Wang Aihua, et al. Synthesis and Identification of [1,2,4]thiadiazole Derivatives As a New Series of Potent and Orally Active Dual Agonists of Peroxisome Proliferator-activated Receptors Alpha and Delta.. J. Med. Chem. Aug 2007;50:3954-63
Abstract
Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. To effectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activate the peroxisome proliferator-activated receptors (PPARs) PPARalpha and PPARdelta simultaneously through a single molecule. Replacement of the methylthiazole of 5 (the PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. Optimization of 13 led to the identification of 24 as a potent and selective PPARalpha/delta dual agonist. Compound 24 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficacies in three animal models may render compound 24 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists and as a potential treatment of the metabolic syndrome.
Mesh Headings (Keywords): Administration, Oral, Animals, Antilipemic Agents, Apolipoprotein A-I, Cell Line, Female, Humans, Insulin Resistance, Male, Mice, Mice, Obese, Mice, Transgenic, PPAR alpha, PPAR delta, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Thiadiazoles
Check for Full Text / PubMed Unique Identifier (PMID): 17608467
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