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 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.
Zask
A
A
Medicinal Chemistry Department, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Jirkovsky
I
I
Nowicki
J W
JW
McCaleb
M L
ML
D000818:Animals; D001786:Blood Glucose; D055598:Chemical Phenomena; D002621:Chemistry; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis*; D007773:Lactates / Q000097:blood; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000627:therapeutic use; D045162:Thiazolidinediones
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007773:Lactates; D009281:Naphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; C063793:5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione; C039671:ciglitazone