Orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2009-06, Vol.19 (11), p.3050-3053
• Main Authors: Koltun, Dmitry O., Vasilevich, Natalya I., Parkhill, Eric Q., Glushkov, Andrei I., Zilbershtein, Timur M., Mayboroda, Elena I., Boze, Melanie A., Cole, Andrew G., Henderson, Ian, Zautke, Nathan A., Brunn, Sandra A., Chu, Nancy, Hao, Jia, Mollova, Nevena, Leung, Kwan, Chisholm, Jeffrey W., Zablocki, Jeff
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Benzyl Compounds - chemical synthesis; Benzyl Compounds - chemistry; Benzyl Compounds - pharmacokinetics; Cell Line, Tumor; Dietary Carbohydrates - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HEPG2 assay; Humans; Microsomal assay; Microsomes, Liver - metabolism; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacokinetics; Rats; Rats, Sprague-Dawley; Saturation index; Stearoyl CoA desaturase (SCD); Stearoyl-CoA Desaturase - antagonists & inhibitors; Stearoyl-CoA Desaturase - metabolism; Tissue Distribution; Tissue partition
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.04.004

We discovered a structurally novel SCD inhibitor CVT-11,563 (IC50 119nM, HEPG2 assay), selective against Δ5 and Δ6 desaturases, with excellent PK parameters (F=90% and dAUC 935ngh/mL). This compound was found to have moderately selective liver distribution and low brain penetration. In a 5-day study CVT-11,563 significantly reduced SCD activity in plasma and liver. We discovered a structurally novel SCD (Δ9 desaturase) inhibitor 4a (CVT-11,563) that has 119nM potency in a human cell-based (HEPG2) SCD assay and selectivity against Δ5 and Δ6 desaturases. This compound has 90% oral bioavailability (rat) and excellent plasma exposure (dAUC 935ngh/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.