Biological activity and preclinical efficacy of azetidinyl pyridazines as potent systemically-distributed stearoyl-CoA desaturase inhibitors

…, S Crane, R Gordon, J Guay, S Guiral, Z Huang…

Index: Isabel, Elise; Powell, David A.; Black, W. Cameron; Chan, Chi-Chung; Crane, Sheldon; Gordon, Robert; Guay, Jocelyne; Guiral, Sebastien; Huang, Zheng; Robichaud, Joel; Skorey, Kathryn; Tawa, Paul; Xu, Lijing; Zhang, Lei; Oballa, Renata Bioorganic and Medicinal Chemistry Letters, 2011 , vol. 21, # 1 p. 479 - 483

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Citation Number: 22

Abstract

Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain tracked closely with skin and eye adverse events. This was attributed to the local SCD inhibition in these tissues as a consequence of the broad tissue distribution observed in mice for this class of ...