Novel spiropiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine]

Bioorg Med Chem Lett. 2010 Jan 15;20(2):746-54. doi: 10.1016/j.bmcl.2009.11.043. Epub 2009 Nov 14.

Abstract

Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3mg/kg) in our preliminary analysis.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacokinetics
  • Cell Line, Tumor
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacokinetics
  • Stearoyl-CoA Desaturase / antagonists & inhibitors*
  • Stearoyl-CoA Desaturase / metabolism

Substances

  • 1'-(6-(5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl)pyridazin-3-yl)-5-(trifluoromethyl)-3,4-dihydrospiro(chromene-2,4'-piperidine)
  • Benzopyrans
  • Piperidines
  • Stearoyl-CoA Desaturase