ABSTRACT
The introduction of a carboxy unit onto dipyrrolyldiketone skeletons was achieved by complexation with arylfluoroboron moieties bearing an acid group. Carboxylate-appended anion-responsive π-electronic molecules, formed upon deprotonation, provided anion-binding self-assemblies, as anionic supramolecular polymers, resulting in ion-pairing assemblies.
ABSTRACT
We previously reported a series of 8-methyl-2-aryl-5-alkylaminoquinolines as a novel class of corticotropin-releasing factor-1 (CRF(1)) receptor antagonists. A critical issue encountered for this series of compounds was low aqueous solubility at physiological pH (pH 7.4). To address this issue, derivatization at key sites (R(2), R(3), R(5), R(5'), and R(8)) was performed and the relationships between structure and solubility were examined. As a result, it was revealed that introduction of a methoxy substituent at the C(8) position had a positive impact on the solubility of the derivatives. Consequently, through in vivo and in vitro biological studies, compound 21d was identified as a potent, orally active CRF(1) receptor antagonist with improved physicochemical properties.
Subject(s)
Aminoquinolines/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Administration, Oral , Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacokinetics , Animals , Behavior, Animal/drug effects , Drug Design , Half-Life , Hydrogen-Ion Concentration , Mice , Mice, Inbred BALB C , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Solubility , Structure-Activity RelationshipABSTRACT
This paper describes the design, synthesis, and structure-activity relationships of a novel series of 7-dialkylamino-3-phenyl-6-methoxy pyrazolo[5,1-b]thiazole derivatives for use as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor. The most promising compound, N-butyl-3-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-6-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[5,1-b][1,3]thiazole-7-amine (6t), showed high affinity (IC(50) = 70 nM) and functional antagonism (IC(50) = 7.1 nM) for the human CRF(1) receptor as well as dose-dependent inhibition of the CRF-induced increase in the plasma adrenocorticotropic hormone (ACTH) concentration at a dose of 30 mg/kg (po). Further, in the light/dark test in mice, the compound 6t showed anxiolytic activity at a dose of 30 mg/kg (po).
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Pyrazoles/chemical synthesis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Thiazoles/chemical synthesis , Administration, Oral , Adrenocorticotropic Hormone/blood , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Cell Line, Tumor , Corticotropin-Releasing Hormone/pharmacology , Cyclic AMP/metabolism , Defecation/drug effects , Drug Design , HEK293 Cells , Humans , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Pyrazoles/chemistry , Pyrazoles/pharmacology , Radioligand Assay , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
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.
