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
  • 1. Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada. Electronic address: [email protected].
  • 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: [email protected].
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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