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)