Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia

J Med Chem. 2011 Jul 28;54(14):5082-96. doi: 10.1021/jm200319u. Epub 2011 Jun 28.

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.

MeSH terms

  • Acetates / chemical synthesis*
  • Acetates / chemistry
  • Acetates / pharmacology
  • Animals
  • Cell Line
  • Diffusion
  • Dogs
  • Female
  • Harderian Gland / metabolism
  • Hep G2 Cells
  • Hepatocytes / metabolism
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Hypolipidemic Agents / chemical synthesis*
  • Hypolipidemic Agents / chemistry
  • Hypolipidemic Agents / pharmacology
  • In Vitro Techniques
  • Liver / enzymology*
  • 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
  • Stearoyl-CoA Desaturase / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tetrazoles / chemical synthesis*
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology
  • Tissue Distribution

Substances

  • (5-(3-(4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)isoxazol-5-yl)-2H-tetrazol-2-yl)acetic acid
  • Acetates
  • Hypoglycemic Agents
  • Hypolipidemic Agents
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Tetrazoles
  • Stearoyl-CoA Desaturase