期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 19, 期 11, 页码 3050-3053出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.04.004
关键词
Stearoyl CoA desaturase (SCD); HEPG2 assay; Microsomal assay; Tissue partition; Tissue distribution; Saturation index
资金
- ASINEX
We discovered a structurally novel SCD (Delta 9 desaturase) inhibitor 4a (CVT-11,563) that has 119 nM potency in a human cell-based (HEPG2) SCD assay and selectivity against Delta 5 and Delta 6 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. (C) 2009 Elsevier Ltd. All rights reserved.
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