Journal of medicinal and pharmaceutical chemistry 2013-01-24

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

Zaihui Zhang, 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

Index: J. Med. Chem. 56(2) , 568-83, (2013)

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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.