title: Plasma-based approach to measure target engagement for liver-targeting stearoyl-CoA desaturase 1 inhibitors.
abstract: A positive correlation between stearoyl-CoA desaturase (SCD)1 expression and metabolic diseases has been reported in rodents and humans. These findings indicate that SCD1 is a promising therapeutic target for the chronic treatment of diabetes and dyslipidemia. The SCD1 enzyme is expressed at high levels in several human tissues and is required for the biosynthesis of monounsaturated fatty acids, which are involved in many biological processes. Liver-targeted SCD inhibitors were designed to pharmacologically manipulate SCD1 activity in the liver to avoid adverse events due to systemic inhibition. This article describes the development of a plasma-based SCD assay to assess the level of SCD inhibition, which is defined in this article as target engagement. Essentially, animals are dosed with an exogenous deuterated tracer (d7-stearic acid) as substrate, and the converted d7-oleic acid product is measured to monitor SCD1 inhibition. This study reveals that this plasma-based assay correlates with liver SCD1 inhibition and can thus have clinical utility.
authors.affiliation: Merck Frosst Canada Ltd., Kirkland, Quebec, Canada. france_landry@sympatico.ca
authors.forename: France
authors.initials: F
authors.lastname: Landry
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Gregoire
authors.initials: G
authors.lastname: Leclair
authors.forename: Chun Sing
authors.initials: CS
authors.lastname: Li
authors.forename: Renata
authors.initials: R
authors.lastname: Oballa
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Kevin
authors.initials: K
authors.lastname: Bateman
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D001681:Biological Assay / Q000379:methods*; D002250:Carbon Radioisotopes / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D003903:Deuterium / Q000032:analysis; D003920:Diabetes Mellitus / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D050171:Dyslipidemias / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D058990:Molecular Targeted Therapy / Q000379:methods; D019301:Oleic Acid / Q000032:analysis* / Q000378:metabolism; D010949:Plasma / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: C561635:(5-(3-(4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)isoxazol-5-yl)-2H-tetrazol-2-yl)acetic acid; D000085:Acetates; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D013777:Tetrazoles; D019301:Oleic Acid; D003903:Deuterium; D013230:Stearoyl-CoA Desaturase