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

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 su...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00167a022