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

Renata M Oballa; Liette Belair; W Cameron Black; Kelly Bleasby; Chi Chung Chan; Carole Desroches; Xiaobing Du; Robert Gordon; Jocelyne Guay; Sebastien Guiral; Michael J Hafey; Emelie Hamelin; Zheng Huang; Brian Kennedy; Nicolas Lachance; France Landry; Chun Sing Li; Joseph Mancini; Denis Normandin; Alessandro Pocai; David A Powell; Yeeman K Ramtohul; Kathryn Skorey; Dan Sørensen; Wayne Sturkenboom; Angela Styhler; Deena M Waddleton; Hao Wang; Simon Wong; Lijing Xu; Lei Zhang

doi:10.1021/jm200319u

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.

Affiliation

¹ Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Québec H9H 3L1, Canada. [email protected]

PMID: 21661758
DOI: 10.1021/jm200319u

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