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At least 739 records · Page 41Linked to original sources
PubMed1983

Antidiabetic activity of some 1-substituted 3,5-dimethylpyrazoles.

Several new 1-substituted 3,5-dimethylpyrazoles were prepared for testing as hypoglycemic agents. A number of these containing para-substituted 1-carbonylphenylurea and para-substituted 1-carbamoylbenzenesulfonylurea derivatives were found to possess potent hypoglycemic activity.

Animals↗
PubMed2001

Reversible carnitine palmitoyltransferase inhibitors with broad chemical diversity as potential antidiabetic agents.

A series of carnitine related compounds of general formula XCH(2)CHZRCH(2)Y were evaluated as CPT I inhibitors in intact rat liver (L-CPT I) and heart mitochondria (M-CPT I). Derivative 27 (ZR = -HNSO(2)R, R = C(12), X = trimethylammonium, Y = carboxylate, (R) form) showed the highest activity (IC(50) = 0.7 microM) along with a good selectivity (M-CPT I/L-CPTI IC(50) ratio = 4.86). Diabetic db/db mice treated orally with 27 showed a significant reduction of serum glucose levels.

3-Hydroxybutyric Acid↗
PubMed2002

Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity.

Synthesis and structure-activity relationships of tricyclic alpha-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARalpha and PPARgamma transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARalpha (EC(50) = 0.36 microM) and PPARgamma (EC(50) = 0.17 microM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARgamma activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARalpha activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.

Animals↗
PubMed2006

GIP(Lys16PAL) and GIP(Lys37PAL): novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potential.

Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys(16)PAL) and GIP(Lys(37)PAL) were resistant to dipeptidyl peptidase IV (DPP IV) degradation. In vitro studies demonstrated that GIP analogues retained their ability to activate the GIP receptor through production of cAMP and to stimulate insulin secretion. Intraperitoneal administration of GIP analogues to obese diabetic (ob/ob) mice significantly decreased the glycemic excursion and elicited increased and prolonged insulin responses compared to native GIP. A protracted glucose-lowering effect was observed 24 h following GIP(Lys(37)PAL) administration. Once a day injection for 14 days decreased nonfasting glucose, improved glucose tolerance, and enhanced the insulin response to glucose. These data demonstrate that fatty acid derivatized GIP peptides represent a novel class of long-acting stable GIP analogues for therapy of type 2 diabetes.

Amino Acid Sequence↗
PubMed1998

4-(trans-4-Methylcyclohexyl)-4-oxobutyric acid (JTT-608). A new class of antidiabetic agent.

During an investigation of drugs for improving the beta-cell response to glucose, we found that 4-cyclohexyl-4-oxobutyric acid selectively improved glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. A series of 4-cycloalkyl-4-oxobutyric acids and related compounds were synthesized and evaluated for their effects on the glucose tolerance test and fasting euglycemia. This study elucidated the structural requirements for drug activity and determined that the optimum compound was 4-(trans-4-methylcyclohexyl)-4-oxobutyric acid 7 (JTT-608). This compound improved glucose tolerance from an oral dose of 3 mg/kg and did not change fasting euglycemia even at an oral dose of 30 mg/kg. Selective improvement of glucose-induced insulin secretion was observed in studies using neonatal streptozotocin rats (nSTZ rats) and perfused pancreases isolated from nSTZ rats.

Animals↗
PubMed1999

Novel antidiabetic and hypolipidemic agents. 3. Benzofuran-containing thiazolidinediones.

Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2, 2,4,6,7-pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the linker between thiazolidinedione and substituted benzofuran pharmacophores showed considerable improvement in their euglycemic activity. Further improvement has been observed when a pyrrolidine moiety is introduced in the structure to give 5-[4-[N-[3(R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6, 7-pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidin-2- ylmethoxy]pheny lene]thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced the plasma glucose and triglyceride to the level of lean littermate, i.e. 8 +/- 1 mM, and is the most potent and efficacious compound reported in this series.

Animals↗
PubMed1999

Novel antidiabetic and hypolipidemic agents. 5. Hydroxyl versus benzyloxy containing chroman derivatives.

Several thiazolidinediones having chroman moieties were synthesized and evaluated for their euglycemic and hypolipidemic activities. Some of the analogues having an aminoalkyl group as a linker between the chroman ring and 4-[5-(2,4-dioxo-1, 3-thiazolidinyl)methyl]phenoxy moiety seem to be better than troglitazone. In vitro transactivation assays of PPARgamma have been carried out with these glitazones to understand their molecular mechanism. For the first time we have found that some of the unsaturated thiazolidinediones are superior to their saturated counterpart in the in vivo assay. A more potent thiazolidinedione analogue than troglitazone is reported. Pharmacokinetic studies have shown that protection of the OH group in the chroman moiety leads to a decrease in metabolism, thereby resulting in a superior pharmacological profile.

Animals↗
PubMedDate not supplied

A constituent of Pterocarpus marsupium, (-)-epicatechin, as a potential antidiabetic agent.

An active constituent of Pterocarpus marsupium, (-)-epicatechin (1), has been reported to reverse hyperglycemia in alloxan diabetic rats when given before or within 24 hr after the dose of alloxan. However, when doses of (-)-epicatechin (30 mg/kg, i.p., twice daily for 3 days) are begun 92 hr after alloxan, there is no significant difference in blood glucose levels between control and (-)-epicatechin treated rats. These data suggest that, although (-)-epicatechin may protect against alloxan toxicity under certain conditions, the usefulness of (-)-epicatechin appears minimal in the treatment of already established diabetic states.

Animals↗