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<p></p> <p><b>New page</b></p><div>AN <br /> 2004:136651 BIOSIS<br /> DN <br /> PREV200400139029<br /> TI <br /> Synthesis and structure-activity relationship for a novel class of potent<br /> and selective carbamoyl-triazole based inhibitors of hormone sensitive<br /> lipase. <br /> AU <br /> Ebdrup, Soren [Reprint Author]; Sorensen, Lotte Gottlieb; Olsen, Ole<br /> Hvilsted; Jacobsen, Poul<br /> CS <br /> Novo Nordisk A/S, Novo Nordisk Park, 2760, Malov, Denmark<br /> sebd@novonordisk.com<br /> SO <br /> Journal of Medicinal Chemistry, (January 15 2004) Vol. 47, No. 2, pp.<br /> 400-410. print. <br /> ISSN: 0022-2623 (ISSN print). <br /> DT <br /> Article<br /> LA <br /> English<br /> ED <br /> Entered STN: 10 Mar 2004<br /> Last Updated on STN: 10 Mar 2004<br /> AB <br /> The central role of the intracellular enzyme hormone-sensitive<br /> lipase (HSL) in regulating fatty acid metabolism makes it an<br /> interesting pharmacological target for the treatment of insulin resistant<br /> and dyslipidemic disorders where a decrease in delivery of fatty acids to<br /> the circulation is desirable, e.g., in individuals with type 2 diabetes,<br /> metabolic syndrome, or impaired glucose tolerance. On the basis of a lead<br /> structure from high throughput screening, we have identified a very potent<br /> type of carbamoyl-triazole inhibitors of HSL. As part of the lead<br /> optimization program, four new classes of carbamoyl-triazoles were<br /> synthesized and tested with respect to potency, efficacy and selectivity.<br /> Methyl-phenyl-carbamoyl-triazoles were identified as potent and<br /> efficacious HSL inhibitors. These compounds do not inhibit other<br /> hydrolases such as hepatic lipase, lipoprotein lipase, pancreatic lipase,<br /> and butyrylcholine esterase. However, the inhibitors 4b and 4g with IC50<br /> values for HSL of 0.17 and 0.25 muM, respectively, were the only<br /> inhibitors selective against acetylcholine esterase. A reversible<br /> pseudosubstrate inhibition mechanism is proposed for this class of<br /> inhibitors.<br /> CC <br /> Enzymes - General and comparative studies: coenzymes 10802<br /> Pathology - Therapy 12512<br /> Metabolism - Metabolic disorders 13020<br /> Endocrine - General 17002<br /> Endocrine - Pancreas 17008<br /> Pharmacology - General 22002<br /> IT <br /> Major Concepts<br /> Endocrine System (Chemical Coordination and Homeostasis); Enzymology<br /> (Biochemistry and Molecular Biophysics); Methods and Techniques;<br /> Pharmaceuticals (Pharmacology)<br /> IT <br /> Diseases<br /> type 2 diabetes: endocrine disease/pancreas, metabolic disease<br /> Diabetes Mellitus, Non-Insulin-Dependent (MeSH)<br /> IT <br /> Chemicals &amp; Biochemicals<br /> carbamoyl-triazole based inhibitors: enzyme inhibitor-drug; hormone<br /> sensitive lipase<br /> IT <br /> Methods &amp; Equipment<br /> drug synthesis: laboratory techniques; structure-activity relationships<br /> analysis: laboratory techniques<br /> RN <br /> 9001-62-1 (hormone sensitive lipase)</div>

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