ABSTRACT
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.
Subject(s)
Pteridines/chemistry , Pyrazines/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Half-Life , Pteridines/chemical synthesis , Pteridines/pharmacokinetics , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Structure-Activity RelationshipABSTRACT
The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 +/- 3.5 ml/min/kg), volume of distribution (2.6 +/- 0.3 l/kg), and half-life (1.2 +/- 0.2 h) of 6-OH-buspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT)(1A) receptor occupancy in a concentration-dependent manner with EC(50) values of 1.0 +/- 0.3 and 0.38 +/- 0.06 microM in the dorsal raphe and 4.0 +/- 0.6 and 1.5 +/- 0.3 microM in the hippocampus, respectively. Both compounds appeared to be approximately 4-fold more potent in occupying presynaptic 5-HT(1A) receptors in the dorsal raphe than the postsynaptic receptors in the hippocampus. Oral dosing of buspirone in rats resulted in exposures (area under the concentration-time profile) of 6-OH-buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP), another major metabolite of buspirone, that were approximately 12 (6-OH-buspirone)- and 49 (1-PP)-fold higher than the exposure of the parent compound. As a whole, these preclinical data suggest that 6-OH-buspirone probably contributes to the clinical efficacy of buspirone as an anxiolytic agent.
Subject(s)
Buspirone/analogs & derivatives , Buspirone/pharmacokinetics , Receptor, Serotonin, 5-HT1A/metabolism , Animals , Area Under Curve , Autoradiography , Biological Availability , Buspirone/blood , Buspirone/metabolism , Buspirone/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Male , Molecular Structure , Piperazines/metabolism , Prosencephalon/drug effects , Prosencephalon/metabolism , Protein Binding/drug effects , Pyridines/metabolism , Raphe Nuclei/drug effects , Raphe Nuclei/metabolism , Rats , Rats, Sprague-Dawley , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacokinetics , Serotonin Receptor Agonists/pharmacology , TritiumABSTRACT
The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.
Subject(s)
Models, Molecular , Pteridines/chemical synthesis , Pyridazines/chemical synthesis , Quantitative Structure-Activity Relationship , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Choroid Plexus/metabolism , Frontal Lobe/metabolism , In Vitro Techniques , Pteridines/chemistry , Pteridines/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Radioligand Assay , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , SwineABSTRACT
The synthesis, evaluation, and structure-activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer's disease gamma-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of gamma-secretase and high potency in cellular assays of A beta reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.
Subject(s)
Caprolactam/chemistry , Endopeptidases/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Succinates/chemistry , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases , Animals , Aspartic Acid Endopeptidases , Caprolactam/analogs & derivatives , Cell Line , Dogs , Drug Design , Drug Evaluation, Preclinical , Endopeptidases/chemistry , Enzyme Inhibitors/chemistry , Humans , Molecular Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.
