Abstract
Structure-activity studies in the pyrazolo[1,5-a]-1,3,5-triazine series led to the discovery that compound 11i (DMP696) is a potent hCRF(1) receptor antagonist (K(i) = 1.7 nM vs 7.5 nM for alpha-hel-CRF(9-41), hCRF(1) adenylate cyclase IC(50) = 82 nM vs 286 nM for alpha-hel-CRF(9-41)). Compound 11i has excellent oral pharmacokinetic profiles in rats and dogs (37% and 50% oral bioavailabilities, respectively). This compound displays good activity in the rat situational anxiety model (MED = 3 mg/kg (po)), whereas a literature standard 1 (CP154526-1) was inactive (MED > 30 mg/kg (po)). Analogue 11i reduced stereotypical mouth movements in rhesus monkeys by 50% at 21 mg/kg (po) using the human intruder paradigm. Overall, the profile of pyrazolotriazine 11i indicates that hCRF(1) receptor antagonists may be anxiolytic agents, which have reduced motor side effect profiles.
MeSH terms
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Administration, Oral
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Animals
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Anti-Anxiety Agents / chemical synthesis
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Anti-Anxiety Agents / pharmacokinetics
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Anti-Anxiety Agents / pharmacology
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Anti-Anxiety Agents / toxicity
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Biological Availability
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Brain / metabolism
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Cardiovascular System / drug effects
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Dogs
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Female
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Gastrointestinal Motility / drug effects
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Humans
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Kidney Function Tests
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Macaca mulatta
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Male
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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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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Respiratory Physiological Phenomena / drug effects
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Structure-Activity Relationship
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Triazines / chemical synthesis*
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Triazines / chemistry
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Triazines / pharmacokinetics
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Triazines / pharmacology
Substances
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Anti-Anxiety Agents
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DMP 696
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Pyrazoles
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Receptors, Corticotropin-Releasing Hormone
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Triazines
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CRF receptor type 1