Abstract
Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC(50) = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V(D) = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.
MeSH terms
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Acenaphthenes
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Adrenocorticotropic Hormone / antagonists & inhibitors
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Animals
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Biological Availability
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Blood-Brain Barrier / metabolism
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Cells, Cultured
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Cyclic AMP / biosynthesis
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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In Vitro Techniques
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Male
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Mice
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Pituitary Gland / cytology
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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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Pyrroles / chemical synthesis*
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
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Receptors, Corticotropin-Releasing Hormone / metabolism
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Stress, Psychological / metabolism
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Structure-Activity Relationship
Substances
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1-(2-chloro-4-methylphenyl)-7-methyl-5-(1-propylbutyl)-1,3,4,5-tetrahydro-1,5,8-triazaacenaphthylene
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2-(2,4-dichlorophenyl)-4-methyl-6-(1-propylbutyl)-2,6,7,8-tetrahydro-1,2,3,6-tetraazaacenaphthylene
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Acenaphthenes
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Heterocyclic Compounds, 3-Ring
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Pyrazoles
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Pyridines
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Pyrroles
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Receptors, Corticotropin-Releasing Hormone
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CRF receptor type 1
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Adrenocorticotropic Hormone
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Cyclic AMP