840490-28-0Relevant articles and documents
Piperazine derivatives and their use as therapeutic agents
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Paragraph 0217; 0230, (2016/03/19)
Compounds for treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the compounds are of formula (I): where x y, W, V, R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.
Discovery of piperazin-1-ylpyridazine-based potent and selective stearoyl-CoA Desaturase-1 inhibitors for the treatment of obesity and metabolic syndrome
Zhang, Zaihui,Sun, Shaoyi,Kodumuru, Vishnumurthy,Hou, Duanjie,Liu, Shifeng,Chakka, Nagasree,Sviridov, Serguei,Chowdhury, Sultan,McLaren, David G.,Ratkay, Leslie G.,Khakh, Kuldip,Cheng, Xing,Gschwend, Heinz W.,Kamboj, Rajender,Fu, Jianmin,Winther, Michael D.
, p. 568 - 583 (2013/04/23)
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 IC50 = 14 nM and HepG2 IC50 = 12 nM) and efficacious in vivo (ED50 = 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.
