Abstract
Expansion of the 6-membered ring and subsequent fine-tuning of the newly obtained 7-membered spiropiperidine structure resulted in the discovery of a series of novel and potent SCD1 inhibitors. Preliminary SAR was explored by modifying an alkyl chain on the azepine nitrogen and resulted in the identification of a highly potent SCD1 inhibitor: 6-[5-(cyclopropylmethyl)-4,5-dihydro-1'H,3H-spiro[1,5-benzoxazepine-2,4'-piperidin]-1'-yl]-N-(2-hydroxy-2-pyridin-3-ylethyl)pyridazine-3-carboxamide (9). Compound 9 exhibited an IC(50) value of 0.01 μM against human SCD1.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Animals
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Drug Discovery*
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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HEK293 Cells
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Humans
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Mice
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Molecular Structure
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Piperidines / chemical synthesis
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Piperidines / chemistry
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Piperidines / pharmacology*
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology*
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Stearoyl-CoA Desaturase / antagonists & inhibitors*
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Stearoyl-CoA Desaturase / metabolism
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Piperidines
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Spiro Compounds
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SCD1 protein, human
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Scd1 protein, mouse
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Stearoyl-CoA Desaturase