View source for BIOSIS / 2004:136651

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