Discovery of piperazin-1-ylpyridazine-based potent and selective stearoyl-CoA desaturase-1 inhibitors for the treatment of obesity and metabolic syndrome

  • J Med Chem. 2013 Jan 24;56(2):568-83. doi: 10.1021/jm301661h.
Zaihui Zhang  1 ,  Shaoyi Sun ,  Vishnumurthy Kodumuru ,  Duanjie Hou ,  Shifeng Liu ,  Nagasree Chakka ,  Serguei Sviridov ,  Sultan Chowdhury ,  David G McLaren ,  Leslie G Ratkay ,  Kuldip Khakh ,  Xing Cheng ,  Heinz W Gschwend ,  Rajender Kamboj ,  Jianmin Fu ,  Michael D Winther
Affiliations
  • 1. Xenon Pharmaceuticals, Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8 Canada.
PMID: 23245208 DOI: 10.1021/jm301661h
Abstract

Stearoyl-CoA desaturase-1 (SCD1) catalyzes de novo synthesis of monounsaturated Fatty Acids from saturated Fatty Acids. Studies have demonstrated that rodents lacking a functional SCD1 gene have an improved metabolic profile, including reduced weight gain, lower triglycerides, and improved Insulin response. In this study, we discovered a series of piperazinylpyridazine-based highly potent, selective, and orally bioavailable compounds. Particularly, compound 49 (XEN103) was highly active in vitro (mSCD1 IC(50) = 14 nM and HepG2 IC(50) = 12 nM) and efficacious in vivo (ED(50) = 0.8 mg/kg). It also demonstrated striking reduction of weight gain in a rodent model. Our findings with small-molecule SCD1 inhibitors confirm the importance of this target in metabolic regulation, describe novel models for assessing SCD1 inhibitors for efficacy and tolerability and demonstrate an opportunity to develop a novel therapy for Metabolic Disease.

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