Abstract
Design, synthesis, and structure-activity relationships of a series of 3-dialkylamino-7-phenyl pyrazolo[1,5-a]pyridines (I) as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor are described. The most prominent compound to emerge from this work, 46 (E2508), exhibits potent in vitro activity, excellent drug-like properties, and robust oral efficacy in animal models of stress-related disorders. It has advanced into clinical trials.
MeSH terms
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Administration, Oral
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Animals
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Antidepressive Agents / chemical synthesis*
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Antidepressive Agents / pharmacokinetics
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Antidepressive Agents / pharmacology
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Biological Availability
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Cyclic AMP / biosynthesis
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HEK293 Cells
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Humans
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Male
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Mice
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Mice, Inbred BALB C
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Microsomes, Liver / metabolism
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Antidepressive Agents
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Pyrazoles
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Pyridines
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Receptors, Corticotropin-Releasing Hormone
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CRF receptor type 1
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Cyclic AMP
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N-(cyclopropylmethyl)-7-(2,6-dimethoxy-4-(methoxymethyl)phenyl)-2-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo(1,5-a)pyridin-3-amine