Biological activity and preclinical efficacy of azetidinyl pyridazines as potent systemically-distributed stearoyl-CoA desaturase inhibitors
2011
Isabel, Elise | Powell, David A. | Black, W Cameron | Chan, Chi-Chung | Crane, Sheldon | Gordon, Robert | Guay, Jocelyne | Guiral, Sebastien | Huang, Zheng | Robichaud, Joël | Skorey, Kathryn | Tawa, Paul | Xu, Lijing | Zhang, Lei | Oballa, Renata
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 compounds. The search for new structural scaffolds which may display a different tissue distribution was initiated. In preparation for an HTS campaign, a radiolabeled azetidinyl pyridazine displaying low non-specific binding in the scintillation proximity assay was prepared.
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