Abstract
A series of novel 2-pyridylbenzimidazole derivatives was rationally designed and synthesized based on our previous studies on benzimidazole 14, a CB1 agonist used as a template for optimization. In the present series, 21 compounds displayed high affinities with Ki values in the nanomolar range. JM-39 (compound 39) was the most active of the series (KiCB1 = 0.53 nM), while compounds 31 and 44 exhibited similar affinities to WIN 55212-2. CoMFA analysis was performed based on the biological data obtained and resulted in a statistically significant CoMFA model with high predictive value (q2 = 0.710, r2 = 0.998, r2pred = 0.823).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacology*
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Benzoxazines / chemistry
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Cannabinoids / chemistry*
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Humans
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Ligands
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Models, Biological
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Morpholines / chemistry
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Naphthalenes / chemistry
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Protein Conformation
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Quantitative Structure-Activity Relationship
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Receptor, Cannabinoid, CB1 / metabolism*
Substances
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2-(2'-pyridyl)benzimidazole
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Benzimidazoles
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Benzoxazines
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Cannabinoids
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Ligands
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Morpholines
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Naphthalenes
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Receptor, Cannabinoid, CB1
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(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone