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)