10 research outputs found
Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice
Direct evidence that hyperglycemia, rather than concomitant increases in known risk factors, induces atherosclerosis is lacking. Most diabetic mice do not exhibit a higher degree of atherosclerosis unless the development of diabetes is associated with more severe hyperlipidemia. We hypothesized that normal mice were deficient in a gene that accelerated atherosclerosis with diabetes. The gene encoding aldose reductase (AR), an enzyme that mediates the generation of toxic products from glucose, is expressed at low levels in murine compared with human tissues. Mice in which diabetes was induced through streptozotocin (STZ) treatment, but not nondiabetic mice, expressing human AR (hAR) crossed with LDL receptor–deficient (Ldlr–/–) C57BL/6 male mice had increased aortic atherosclerosis. Diabetic hAR-expressing heterozygous LDL receptor–knockout mice (Ldlr+/–) fed a cholesterol/cholic acid–containing diet also had increased aortic lesion size. Lesion area at the aortic root was increased by STZ treatment alone but was further increased by hAR expression. Macrophages from hAR-transgenic mice expressed more scavenger receptors and had greater accumulation of modified lipoproteins than macrophages from nontransgenic mice. Expression of genes that regulate regeneration of glutathione was reduced in the hAR-expressing aortas. Thus, hAR increases atherosclerosis in diabetic mice. Inhibitors of AR or other enzymes that mediate glucose toxicity could be useful in the treatment of diabetic atherosclerosis
Novel euglycemic and hypolipidemic agents: Pyridine containing unsaturated thiazolidinediones
403-406Pyridyl containing
2,4-thiazolidinediones having cyclic amine as linker have been synthesized.
Both unsaturated thiazolidinedione
<span style="font-size:15.5pt;
mso-bidi-font-size:8.5pt;font-family:" times="" new="" roman";mso-fareast-font-family:="" "times="" roman";mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">6<span style="font-size:15.5pt;mso-bidi-font-size:
8.5pt;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">
and saturated thiazolidinedione 5 and their various salts have been evaluated
in db/db mice for euglycemic and hypolipidemic effects. The maleate salt of TZD
6a is found to be a very potent euglycemic
and hypolipidemic compound.</span
(−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic Acid [(−)DRF 2725]: A Dual PPAR Agonist with Potent Antihyperglycemic and Lipid Modulating Activity
PAT5A: A Partial Agonist of Peroxisome Proliferator-Activated Receptor γ Is a Potent Antidiabetic Thiazolidinedione Yet Weakly Adipogenic
Effects of lipoprotein lipase and statins on cholesterol uptake into heart and skeletal muscle
BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder
There
is a significant unmet medical need for more efficacious
and rapidly acting antidepressants. Toward this end, negative allosteric
modulators of the <i>N</i>-methyl-d-aspartate receptor
subtype GluN2B have demonstrated encouraging therapeutic potential.
We report herein the discovery and preclinical profile of a water-soluble
intravenous prodrug BMS-986163 (<b>6</b>) and its active parent
molecule BMS-986169 (<b>5</b>), which demonstrated high binding
affinity for the GluN2B allosteric site (<i>K</i><sub>i</sub> = 4.0 nM) and selective inhibition of GluN2B receptor function (IC<sub>50</sub> = 24 nM) in cells. The conversion of prodrug <b>6</b> to parent <b>5</b> was rapid in vitro and in vivo across preclinical
species. After intravenous administration, compounds <b>5</b> and <b>6</b> have exhibited robust levels of ex vivo GluN2B
target engagement in rodents and antidepressant-like activity in mice.
No significant off-target activity was observed for <b>5</b>, <b>6</b>, or the major circulating metabolites <b>met-1</b> and <b>met-2</b>. The prodrug BMS-986163 (<b>6</b>)
has demonstrated an acceptable safety and toxicology profile and was
selected as a preclinical candidate for further evaluation in major
depressive disorder