Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors

Dmitry O Koltun; Eric Q Parkhill; Natalya I Vasilevich; Andrei I Glushkov; Timur M Zilbershtein; Alexei V Ivanov; Andrew G Cole; Ian Henderson; Nathan A Zautke; Sandra A Brunn; Nevena Mollova; Kwan Leung; Jeffrey W Chisholm; Jeff Zablocki

doi:10.1016/j.bmcl.2009.02.019

Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors

Bioorg Med Chem Lett. 2009 Apr 1;19(7):2048-52. doi: 10.1016/j.bmcl.2009.02.019. Epub 2009 Feb 8.

Authors

Dmitry O Koltun¹, Eric Q Parkhill, Natalya I Vasilevich, Andrei I Glushkov, Timur M Zilbershtein, Alexei V Ivanov, Andrew G Cole, Ian Henderson, Nathan A Zautke, Sandra A Brunn, Nevena Mollova, Kwan Leung, Jeffrey W Chisholm, Jeff Zablocki

Affiliation

¹ Department of Medicinal Chemistry, CV Therapeutics, Inc., Palo Alto, CA 94304, USA. dmitry.koltun@cvt.com

PMID: 19249203
DOI: 10.1016/j.bmcl.2009.02.019

Abstract

We identified a series of structurally novel SCD (Delta9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC(50) value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Delta5 and Delta6 desaturases.

MeSH terms

Animals
Cell Line
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Humans
Inhibitory Concentration 50
Microsomes / metabolism
Pteridines / chemistry*
Pteridines / metabolism
Pteridines / pharmacology
Quinoxalines / chemistry*
Quinoxalines / pharmacology
Rats
Stearoyl-CoA Desaturase / antagonists & inhibitors*
Stearoyl-CoA Desaturase / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Pteridines
Quinoxalines
Stearoyl-CoA Desaturase