Novel Euglycemic and Hypolipidemic Agents. 4. Pyridyl- and Quinolinyl-Containing Thiazolidinediones

Abstract

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.

Synthesis of Silicon and Germanium Containing Heteroaromatic Sulfides as Cholesterol Level Lowering and Vasodilating Agents

“…Thus 2-[(y-tdmethylsilylpropyl)thio] derivatives of pyridine 4a and quinoline 6a are more active than the similar derivatives of 4-pyddine 5a and 8-quinoline 7a. (15) '.. The studied compounds have a medium toxicity.…”

“…For example, pyridine sulfides display cholesterol acyltransferase inhibitor [1], blood sugar reduction [2], vasodilating [3][4][5][6][7], vasopressing [8], antihypertensive [4,5,7,9,10], hypotensive [6], hypoglycemic [11][12][13], anticholesteremic [14], euglicemic and hypolipidemic [15], cardiotonic [16], cardiovascular and cardioprotective [17] activities. Quinoline sulfides exhibit vasodilating [18][19][20][21][22][23][24], antihypertensive [18,19], hypotensive [23,30], euglicemic and hypolipidemic [15], antithrombotic [31,32] and cardiotonic [32] activities. Thiazole and benzothiazole sulfides display vasodilating [33][34][35], and hypotensive [35] activities and may be used as hypolipemics and in treatment of arteriosclerosis [36].…”

Thiazolidine-2,4-Diones: An Update Review of Antidiabetic Agents

“…Pharmacokinetic studies of (53) were also reported 68 . Furthermore, the comparative studies between rosiglitazone (4) and PAT5A (53) indicates that, in contrast to rosiglitazone (4), PAT5A (53) inhibits biosynthesis of cholesterol and fatty acid.…”

“…▪ The brief review of thiazolidine-2,4-diones were shown that, introduction of several heterocyclic rings are mainly containing nitrogen atom at the lipophilic tail region were identified to have promising glucose lowering activity. These different heterocyclic rings are containing different thiazolidine-2,4-diones such as rosiglitazone (4) 11 , pioglitazone (5) 95 , lobeglitazone (6) 28 , darglitazone (9) 32 , rivoglitazone (11) 36 , mitoglitazone (13) 41,42 , balaglitazone (15) 46 , AD-5061/AD-7057 (20) 20 , DRF-2189 (21) 51 , edaglitazone (25) 56 , PHT46 (28) 58 , PMT13 (29) 13 , DRF-2519 (39) 62 , PAT5A (53) 68 and (54). 70 ▪ Furthermore, in case of different aromatic rings substitutions present at lipophilic tail region of thiazolidine-2,4-diones were shown phenyl ring with H-bond acceptor substitution.…”

Oral bioavailability and Pharmacokinetics of PAT-5A, a new insulin sensitizer in rats

“…PAT-5A showed better glucose and lipid lowering properties than troglitazone and rosiglitazone in different diabetic and dyslipidemic animal models (10)(11)(12). Probe toxicity studies of PAT-5A in Wistar rats showed better tolerance than rosiglitazone (12).…”