Novel euglycemic and hypolipidemic agents. 4. Pyridyl- and quinolinyl-containing thiazolidinediones.
A series of substituted pyridyl- and quinolinyl-containing 2, 4-thiazolidinediones having interesting cyclic amine as a linker have been synthesized. Both unsaturated thiazolidinediones 5 and saturated thiazolidinediones 6 and their various salts were evaluated in db/db mice for euglycemic and hypolipidemic effects and compared with BRL compound 11 and BRL-49653, respectively. Some of the potent compounds were converted to various salts in order to obtain improved activities. Among all the salts evaluated, the maleate salt of unsaturated TZD 5a was found to be a very potent euglycemic and hypolipidemic compound. Some of the more interesting compounds have also been evaluated in ob/ob mice and compared with rosiglitazone (maleate salt of BRL-49653). Oral glucose tolerance tests were performed in both db/db and ob/ob mice. Pharmacokinetic studies of 5a maleate are also reported. Receptor binding studies of PPARgamma by 5a/5a maleate did not show any significant transactivation of PPARalpha or PPARgamma.
Departments of Medicinal Chemistry and Drug Discovery, Pharmacology, and Pharmacokinetics, Dr. Reddy's Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India. bblohray@icenet.net
B B
BB
Lohray
V
V
Bhushan
A S
AS
Reddy
P B
PB
Rao
N J
NJ
Reddy
P
P
Harikishore
N
N
Haritha
R K
RK
Vikramadityan
R
R
Chakrabarti
R
R
Rajagopalan
K
K
Katneni
D000818:Animals; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045162:Thiazolidinediones
C120311:5-(4-((1-(pyridin-2-yl)pyrrolidin-2-yl)methoxy)phenylmethylene)thiazolidine-2,4-dione; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D011725:Pyridines; D011804:Quinolines; D013844:Thiazoles; D045162:Thiazolidinediones