Abstract
The continuing investigation of SAR studies of 3-(2-hydroxyethoxy)-N-(5-benzylthiazol-2-yl)-benzamides as stearoyl-CoA desaturase-1 (SCD-1) inhibitors is reported. Our prior hit-to-lead effort resulted in the identification of 1a as a potent and orally efficacious SCD-1 inhibitor. Further optimization of the structural motif resulted in the identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (37c) with sub nano molar IC(50) in both murine and human SCD-1 inhibitory assays. This compound demonstrated a dose-dependent decrease in the plasma desaturation index in C57BL/6J mice on a non-fat diet after 7 days of oral administration.
MeSH terms
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Administration, Oral
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Animals
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Area Under Curve
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Benzamides / chemical synthesis*
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Benzamides / pharmacology
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Chemistry, Pharmaceutical / methods*
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Dose-Response Relationship, Drug
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Humans
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Inhibitory Concentration 50
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Mice
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Mice, Inbred C57BL
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Models, Chemical
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Stearoyl-CoA Desaturase / antagonists & inhibitors*
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Stearoyl-CoA Desaturase / chemistry
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacology
Substances
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3-(2-hydroxyethoxy)-4-methoxy-N-(5-(3-trifluoromethylbenzyl)thiazol-2-yl)benzamide
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Benzamides
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Enzyme Inhibitors
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Thiazoles
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Stearoyl-CoA Desaturase