Synthesis and antihyperglycemic activity of novel 5-(naphthalenylsulfonyl)-2,4-thiazolidinediones

• Published in: Journal of medicinal chemistry 1990-05, Vol.33 (5), p.1418-1423
• Main Authors: Zask, Arie, Jirkovsky, Ivo, Nowicki, James W, McCaleb, Michael L
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose; Chemical Phenomena; Chemistry; Diabetes Mellitus, Type 2 - drug therapy; Hypoglycemic Agents - chemical synthesis; Lactates - blood; Male; Mice; Naphthalenes - chemical synthesis; Naphthalenes - therapeutic use; Rats; Rats, Zucker; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - therapeutic use; Thiazolidinediones
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00167a022

A series of 5-(naphthalenylsulfonyl)-2,4-thiazolidinediones were synthesized and evaluated for antihyperglycemic activity in an insulin-resistant, genetically diabetic db/db mouse model of non-insulin-dependent diabetes mellitus (NIDDM). The sulfones could be synthesized by a novel, selective C-5 sulfonylation of dilithio-2,4-thiazolidinedione with appropriate sulfonyl chlorides. Within this series, naphthalene was found to be superior to other groups for eliciting antihyperglycemic activity, including the p-alkoxyphenyl group found in ciglitazone, a prototypical agent for this activity. Attachment of the 5-sulfonyl-2,4-thiazolidinedione moiety to the 2-naphthalene position led to optimum activity. Other linkers between the naphthalene and 2,4-thiazolidinedione rings, such as thio, methylene, oxy, and sulfinyl led to decreased antihyperglycemic activity. The best analogue, 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione (AY-31,637) was equipotent to ciglitazone in two animal models of NIDDM.