Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones as antihyperglycemic agents.
Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-(3-aryl-2-propynyl)-5-(arylsulfanyl)thiazolidine-2,4-diones were prepared and evaluated as oral antihyperglycemic agents in the obese, insulin resistant db/db mouse model at 100 mg/kg and, if the analogue had sufficient potency, 20 mg/kg. The sulfonylthiazolidinediones, 2, were more potent than the corresponding sulfanylthiazolidinedione congeners, 1. With regard to substituent effects on the 3-propynyl phenyl ring (Ar') of 2, 4-halogen substitution generally resulted in the more potent analogues. Substituent effects on the phenylsulfonyl moiety (Ar) of 2 were less clear, although para-halogen substitution on Ar generally was preferable. 2-Pyridinesulfonyl derivatives (Ar = 2-pyridine in 2) also had good potency. Several compounds from series 2 were effective at lowering glucose and insulin in the obese, insulin resistant ob/ob mouse at the 50 mg/kg oral dose. Compound 20 significantly improved the glucose tolerance of obese, insulin resistant Zucker rats at the 20 mg/kg dose level and had no effect on plasma glucose or on glucose tolerance in normal rats fasted for 18 h at the 100 mg/kg level.
Wrobel
J
J
Wyeth-Ayerst Research, Inc., Princeton, New Jersey 08543-8000, USA.
Li
Z
Z
Dietrich
A
A
McCaleb
M
M
Mihan
B
B
Sredy
J
J
Sullivan
D
D
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011924:Rats, Zucker; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013450:Sulfones; D013844:Thiazoles