Structure–activity studies on 4-substituted-2-anilinopyrimidine corticotropin releasing factor (CRF) antagonists

Structure–activity studies around the 4-position of 2-anilinopyrimidine corticotropin releasing factor (CRF) antagonists suggest that there is a large lipophilic cavity in the rat CRF receptor, which can accommodate a wide variety of substituents at this position in contrast to the steric constraint...

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Published in:Bioorganic & medicinal chemistry 1999-11, Vol.7 (11), p.2321-2328
Main Authors: Gilligan, Paul J., He, Liqi, Culp, Steven, Fitzgerald, Lawrence, Tam, S.William, Wong, Y.Nancy
Format: Article
Language:English
Subjects:
Adenylyl Cyclase Inhibitors
Aniline Compounds - pharmacology
Animals
antagonists
Biological and medical sciences
Corticotropin releasing factor
Corticotropin-Releasing Hormone - antagonists & inhibitors
Corticotropin-Releasing Hormone - metabolism
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Pyrimidines - pharmacology
Rats
receptor
Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors
Structure-Activity Relationship
substituent effects
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Summary:Structure–activity studies around the 4-position of 2-anilinopyrimidine corticotropin releasing factor (CRF) antagonists suggest that there is a large lipophilic cavity in the rat CRF receptor, which can accommodate a wide variety of substituents at this position in contrast to the steric constraints observed for other positions on the 2-anilinopyrimidine core. The chemical syntheses and biological activities of 2-anilinopyrimidine CRF antagonists with carbon-linked substituents at the 4-position are reported. Significant improvements in rat pharmacokinetic parameters were achieved relative to those for the lead structure. While the lead compound 1 (rCRF Ki=44 nM) afforded no detectable rat plasma levels after intraperitoneal (ip) or oral (po) dosing, compounds 3 -3 (rCRF Ki=16 nM) and 3-4 (rCRF Ki=59 nM) gave high rat plasma levels at 30 mg/kg (ip, po) (Cmax=1389 nM and 8581 nM (ip) respectively; Cmax=113 nM and 988 nM (po), respectively). Furthermore 3-3 and 3-4 had superior bioavailabilities at these doses (59 and 46% (ip), respectively; 2 and 10% (po), respectively).
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(99)00182-0