Orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors.
Basic Information
ID: ALA1136871
Journal: Bioorg Med Chem Lett
Title: Orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors.
Authors: Koltun DO, Vasilevich NI, Parkhill EQ, Glushkov AI, Zilbershtein TM, Mayboroda EI, Boze MA, Cole AG, Henderson I, Zautke NA, Brunn SA, Chu N, Hao J, Mollova N, Leung K, Chisholm JW, Zablocki J.
Abstract: We discovered a structurally novel SCD (Delta9 desaturase) inhibitor 4a (CVT-11,563) that has 119 nM potency in a human cell-based (HEPG2) SCD assay and selectivity against Delta5 and Delta6 desaturases. This compound has 90% oral bioavailability (rat) and excellent plasma exposure (dAUC 935 ng h/mL). Additionally, 4a shows moderately selective liver distribution (three times vs plasma and adipose tissue) and relatively low brain penetration. In a five-day study (high sucrose diet, rat) compound 4a significantly reduced SCD activity as determined by GC analysis of fatty acid composition in plasma and liver. We describe the discovery of 4a from HTS hit 1 followed by scaffold replacement and SAR studies focused on DMPK properties.
CiteXplore: 19394219
DOI: 10.1016/j.bmcl.2009.04.004
Patent ID: ┄