2. Academic Validation
  3. Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases

Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases

  • Bioorg Med Chem Lett. 2014 Jan 15;24(2):520-5. doi: 10.1016/j.bmcl.2013.12.036.
Shaoyi Sun 1,  Zaihui Zhang 2,  Vishnumurthy Kodumuru 2,  Natalia Pokrovskaia 2,  Julia Fonarev 2,  Qi Jia 2,  Po-Yee Leung 3,  Jennifer Tran 3,  Leslie G Ratkay 2,  David G McLaren 2,  Chris Radomski 2,  Sultan Chowdhury 2,  Jianmin Fu 2,  Brian Hubbard 3,  Michael D Winther 2,  Natalie A Dales 4
Affiliations

Affiliations

  • 1 Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada. Electronic address: ssun@xenon-pharma.com.
  • 2 Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
  • 3 Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • 4 Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA. Electronic address: natalie.dales@novartis.com.
PMID: 24374272 DOI: 10.1016/j.bmcl.2013.12.036
Abstract

Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compound 5. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 (compound 22) was identified after optimization of the thiazolylimidazolidinone series. This compound demonstrated a 560-fold improvement in in vitro potency and reduced plasma desaturation indices in a dose dependent manner, with an EC50 of 4.5 mg/kg.

Keywords

Amide bioisosteres; Desaturation index; SCD1 inhibitors; Stearoyl-CoA desaturase-1; Thiazolylimidazolidinone.

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