Design and synthesis of the first generation of dithiolane thiazolidinedione- and phenylacetic acid-based PPARgamma agonists.
A series of novel derivatives of potent antioxidant vitamin, alpha-lipoic acid, and related analogues were designed, synthesized, and evaluated for their PPARgamma agonist activities. Compounds 9a and the water soluble analogue11e were found to be potent PPARgamma agonists. Compound 9a appeared to have a significant role in improving insulin sensitivity and reducing triglyceride levels in fa/fa rats as well as inhibited proliferation of a variety of normal and neoplastic cultured human cell types. These novel compounds may prove efficacious not only in the treatment of Type 2 diabetes, but also atherosclerosis, prevention of vascular restenosis, and inflammatory skin diseases.
Chittiboyina
Amar G
AG
Laboratory for Applied Drug Design and Synthesis, Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, 38677, USA.
Venkatraman
Meenakshi S
MS
Mizuno
Cassia S
CS
Desai
Prashant V
PV
Patny
Akshay
A
Benson
Stephen C
SC
Ho
Christopher I
CI
Kurtz
Theodore W
TW
Pershadsingh
Harrihar A
HA
Avery
Mitchell A
MA
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007333:Insulin Resistance; D007378:Interleukins / Q000096:biosynthesis; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000494:pharmacology; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D000960:Hypolipidemic Agents; D007378:Interleukins; C513152:N-(2-(4-((2,4-dioxo-1,3-thiazolidin-5-yl)methyl)phenoxy)ethyl)-5-(1,2-dithiolan-3-yl)-N-methylpentanamide; D047495:PPAR gamma; D010648:Phenylacetates; D045162:Thiazolidinediones; D008063:Thioctic Acid