Discovery of triazolone derivatives as novel, potent stearoyl-CoA desaturase-1 (SCD1) inhibitors

  • Bioorg Med Chem. 2015 Feb 1;23(3):455-65. doi: 10.1016/j.bmc.2014.12.014.
Shaoyi Sun  1 ,  Zaihui Zhang  2 ,  Natalia Pokrovskaia  2 ,  Sultan Chowdhury  2 ,  Qi Jia  2 ,  Elaine Chang  2 ,  Kuldip Khakh  2 ,  Rainbow Kwan  2 ,  David G McLaren  2 ,  Chris C Radomski  2 ,  Leslie G Ratkay  2 ,  Jianmin Fu  2 ,  Natalie A Dales  3 ,  Michael D Winther  2
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, 250 Massachusetts Ave, Cambridge, MA 02139, USA. Electronic address: [email protected].
PMID: 25555732 DOI: 10.1016/j.bmc.2014.12.014
Abstract

Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and Cancer. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6 mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in Metabolic Disease settings.

Keywords
Desaturation index; Pyrazolyltriazolone; Stearoyl-CoA desaturase; Thiazolytriazolone.
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