title: Synthesis and structure-activity relationship for a novel class of potent and selective carbamate-based inhibitors of hormone selective lipase with acute in vivo antilipolytic effects.
abstract: Hormone-sensitive lipase (HSL) is an intracellular enzyme that has a central role in the regulation of fatty acid metabolism. The enzyme, therefore, is a potentially interesting pharmacological target for the treatment of insulin resistance and dyslipidemic disorders. Based on a high throughput screening, a carbamate based HSL inhibitor was identified and optimized into the selective HSL inhibitors 4-hydroxymethyl-piperidine-1-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester (13f) and 4-hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester (13g), with IC50 values of 110 and 500 nM, respectively. Both inhibitors were active in acute antilipolytic experiments in vivo and none of the inhibitors inhibited the cytochrome P450 (CYP) isoforms 2D6, 3A4, and 1A2.
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark. sebdrup@yahoo.dk
authors.forename: Søren
authors.initials: S
authors.lastname: Ebdrup
authors.forename: Hanne Hoffmann Frølund
authors.initials: HH
authors.lastname: Refsgaard
authors.forename: Christian
authors.initials: C
authors.lastname: Fledelius
authors.forename: Poul
authors.initials: P
authors.lastname: Jacobsen
mesh_terms: D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D005990:Glycerol / Q000097:blood; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008066:Lipolysis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D002787:Sterol Esterase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C524713:4-hydroxymethylpiperidine-1-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)phenyl ester; C524714:4-hydroxypiperidine-1-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)phenyl ester; D002219:Carbamates; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D010880:Piperidines; D011725:Pyridines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002787:Sterol Esterase; D005990:Glycerol