Abstract
We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
MeSH terms
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Amides / chemical synthesis
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Amides / chemistry*
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Amides / pharmacokinetics
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Amides / pharmacology*
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Animals
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Biphenyl Compounds / chemical synthesis*
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacokinetics
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Biphenyl Compounds / pharmacology*
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Brain / drug effects
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Brain / metabolism
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Cattle
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Computational Biology
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Humans
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Ligands
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Models, Molecular
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Molecular Structure
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Receptors, Somatostatin / antagonists & inhibitors*
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Receptors, Somatostatin / chemistry
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Receptors, Somatostatin / metabolism
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Structure-Activity Relationship
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Sulfur / chemistry
Substances
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Amides
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Biphenyl Compounds
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Ligands
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MCHR1 protein, human
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Receptors, Somatostatin
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SB-568849
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Sulfur