Peroxisome proliferators-activated receptors (PPARs) are a subfamily of nuclear hormone receptors, which are ligandactivated transcription factors. There are three subtypes of PPAR: PPARa expressed in the liver and related to fatty acid metabolism, PPARg expressed in adipocytes and playing a role in its differentiation, and PPARd expressed in most cell types and involved in dyslipidemia, cancer and the central nervous system; therefore, PPARs have been focused on as a potential target for metabolic diseases such as diabetes, dyslipidemia and atherosclerosis.1-3) Fibrates such as clofibrate, bezafibrate and fenofibrate, which have been long and widely used as anti-hyperlipidemic drugs, are known to exert their effect via activation of PPARa. Thiazolidinedione derivatives (glitazones), such as pioglitazone and rosiglitazone, known as anti-diabetic drugs, activate PPARg and enhance insulin sensitivity. 4,5) Thiazolidinedione derivatives cause edema, increase the risk of weight gain and congestive heart failure, and rarely show hepatotoxicity.6,7) There have been a great number of attempts to find a novel PPARg agonist that is structurally different from thiazolidinedione derivatives and has higher efficacy and safety. Thiazolidinedione moiety was replaced by oxadiazolidinedione and isoxazolidinedione in YM-440 and JTT-501, respectively (Fig. 1). 8,9) Endogenous ligands for PPARg have been reported to be fatty acids and eicosanoids, such as 15-deoxy-D 12,14 -prostaglandin J 2 .2,10) Thus, a number of carboxylic acid derivatives have been designed and synthesized to enhance drug-protein interaction and to modify PPAR subtype selectivity ( Fig. 1) 2, [11][12][13] ; however, no nonthiazolidinedione derivatives have been developed successfully as new anti-diabetic drugs; therefore, further efforts are necessary to identify a structurally new PPARg agonist.As shown in Fig. 1, some recent PPARg agonists are benzene derivatives with carboxylic acid moiety and two lipophilic moieties, which are postulated to have lipophilic interaction with two regions of a PPARg protein.14) However, in these compounds, a carboxylic acid moiety, lipophilic moiety and benzyl moiety with a lipophilic chain are attached to a central atom (C or N) via a single bond, thus, each moiety can bend and/or rotate freely (Fig. 1). We hypothesized that in these carboxylic acid-type derivatives, the limitation of movement of the three moieties and fixation of their direction may enhance their PPARg agonist activity and reduce their side effects. In the present study, a tyrosine derivative was cyclized to a 1,2,3,4-tetrahydroisoquinoline derivative and then various side chains were introduced into the 2nd and 7th positions of the 1,2,3,4-tetrahydroisoquinoline ring (Fig. 2). Biological activities were evaluated in a series of 1,2,3,4-tetrahydroisoquinoline derivatives and their structure-activity relationships are discussed.Chemistry The general approach to the synthesis of (S)-2-substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives 19 ...

Diabetes is a risk factor of ischemic heart disease, cerebral ischemia, and atherosclerosis, in which endothelial dysfunction plays a role in the pathogenesis. We examined vascular responses in the aorta of pre-diabetic db/db mice with normoglycemia, hyperlipidemia, and hyperinsulinemia (6 weeks old), and diabetic db/db mice with hyperglycemia, hyperlipidemia, and hyperinsulinemia (11 weeks old) in comparison with age-matched non-diabetic db/+ mice. Prostaglandin F2alpha (PGF2alpha)-induced contraction was significantly enhanced in the aorta of diabetic but not pre-diabetic db/db mice compared to age-matched non-diabetic db/+ mice. Acetylcholine (ACh), adenosine-5'-diphosphate (ADP), NaF, a G protein activator and A-23187, a Ca-ionophore, caused endothelium-dependent and nitric oxide (NO)-mediated relaxation, and sodium nitroprusside (SNP), an NO donor, caused endothelium-independent relaxation in the pre-contracted aorta of db/db mice. Maximal endothelium-dependent ACh-induced relaxation was reduced in diabetic but not pre-diabetic db/db mice compared to age-matched db/+ mice, while maximal SNP-induced relaxation was not different between diabetic and non-diabetic mice. ACh-induced relaxation in diabetic db/db mice was not affected by ozagrel, a thromboxane A2 (TXA2) synthetase inhibitor, or acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor, suggesting no involvement of endogenous TXA2 or prostanoids in the reduction of relaxation. Maximal endothelium-dependent ADP-, A-23187-, and NaF-induced relaxation was not reduced in diabetic db/db mice. EC50 values for ACh- and SNP-induced relaxation were increased in diabetic but not pre-diabetic db/db mice, suggesting decreases in sensitivity to NO in diabetic mice. Two-week treatment with KV-5070, a PPARgamma agonist, lowered plasma glucose, triglyceride (TG), and insulin but not cholesterol, and reversed the reduced ACh-induced relaxation. In conclusion, ACh-induced endothelium-dependent relaxation is impaired in diabetic db/db mice, probably due to the dysfunction of ACh receptors and/or receptor-G protein coupling. Endothelial dysfunction was not genetic and was considered to be initiated primarily by hyperglycemia, and was improved by anti-diabetic treatment with a PPARgamma agonist.

A novel series of 2,7-substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2-Furylacryloyl)-7-[2-(2-methylindane-2-yl)-5-methyloxazol-4-yl] methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butylamine salt (13jE) was identified as a potent human peroxisome proliferator-activated receptor γ (PPARγ)-selective agonist (EC 50 85 nM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC 50 1.0 µM). Compound 13jE partially activated PPARγ, but not PPARα or PPARδ, and antagonized farglitazar, a full PPARγ agonist. C max after the oral administration of 13jE at 10 mg/kg was 28.6 µg/mL (53 µM) in male Sprague-Dawley (SD) rats. Repeated administration of 13jE and rosiglitazone for 14 d at 10 mg/kg/d decreased plasma glucose and triglyceride levels significantly in male KK-A y mice. Rosiglitazone, but not 13jE, significantly increased the plasma volume and liver weight. In conclusion, 13jE showed stronger hypoglycemic and hypolipidemic effects and weaker hemodilution and hepatotoxic effects than rosiglitazone, suggesting that its safer efficacy may be due to its partial PPARγ agonism and PTP-1B inhibition.

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