title: Biological activity and preclinical efficacy of azetidinyl pyridazines as potent systemically-distributed stearoyl-CoA desaturase inhibitors.
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 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.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada. elise_isabel@merck.com
authors.forename: Elise
authors.initials: E
authors.lastname: Isabel
authors.forename: David A
authors.initials: DA
authors.lastname: Powell
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Sheldon
authors.initials: S
authors.lastname: Crane
authors.forename: Robert
authors.initials: R
authors.lastname: Gordon
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Guay
authors.forename: Sebastien
authors.initials: S
authors.lastname: Guiral
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Joël
authors.initials: J
authors.lastname: Robichaud
authors.forename: Kathryn
authors.initials: K
authors.lastname: Skorey
authors.forename: Paul
authors.initials: P
authors.lastname: Tawa
authors.forename: Lijing
authors.initials: L
authors.lastname: Xu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Renata
authors.initials: R
authors.lastname: Oballa
mesh_terms: D000818:Animals; D001384:Azetidines / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D051379:Mice; D011485:Protein Binding; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001384:Azetidines; D004791:Enzyme Inhibitors; D011724:Pyridazines; D013230:Stearoyl-CoA Desaturase