ABSTRACT
The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.
Subject(s)
Acetates/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Liver/enzymology , Stearoyl-CoA Desaturase/antagonists & inhibitors , Tetrazoles/chemical synthesis , Acetates/chemistry , Acetates/pharmacology , Animals , Cell Line , Diffusion , Dogs , Female , Harderian Gland/metabolism , Hep G2 Cells , Hepatocytes/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , In Vitro Techniques , Liver-Specific Organic Anion Transporter 1 , Macaca mulatta , Male , Mice , Mice, Inbred C57BL , Microsomes/metabolism , Organic Anion Transporters/metabolism , Organic Anion Transporters, Sodium-Independent/metabolism , Rats , Rats, Sprague-Dawley , Skin/metabolism , Solute Carrier Organic Anion Transporter Family Member 1B3 , Species Specificity , Structure-Activity Relationship , Tetrazoles/chemistry , Tetrazoles/pharmacology , Tissue DistributionABSTRACT
SCD1 inhibition may represent a novel treatment for obesity, type-2 diabetes and related metabolic disorders. A prototype thiazole amide analog 13 (MF-152) was identified as an excellent tool in the study of SCD biology in animals.
