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

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

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, 250 Massachusetts Ave, Cambridge, MA 02139, USA. Electronic address: natalie.dales@novartis.com.
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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