ABSTRACT
A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Quinolines/pharmacology , Animals , Biological Availability , Dogs , Drug Evaluation, Preclinical , Macaca mulatta , Quinolines/chemistry , Quinolines/pharmacokinetics , RatsABSTRACT
Previously, chemistry effort on the gem-cyclohexane series of gamma-secretase inhibitors has focused on the 4-position of the cyclohexane ring. Recently chemistry has been directed towards the 3-position and substitution here has also provided compounds with high gamma-secretase activity.
Subject(s)
Alzheimer Disease/pathology , Cyclohexanes/chemistry , Endopeptidases/metabolism , Protease Inhibitors/chemistry , Sulfones/chemistry , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases , Aspartic Acid Endopeptidases , Cyclohexanes/pharmacology , Humans , Inhibitory Concentration 50 , Models, Chemical , Protease Inhibitors/pharmacology , Stereoisomerism , Sulfones/pharmacologyABSTRACT
A new class of high affinity hNK1R antagonists based on seven-membered ring cores has been identified. This series, with relatively simple, compact structures, includes compounds with high affinity, good selectivity, and promising in vivo properties.
Subject(s)
Lactams/chemistry , Neurokinin-1 Receptor Antagonists , Cell Line , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABA(A)alpha5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of alpha5- over alpha1-, alpha2-, and alpha3-containing GABA(A) receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABA(A)alpha5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABA(A)alpha5 subtype with functional selectivity over the other GABA(A) receptor subtypes and good oral bioavailability.
Subject(s)
GABA-A Receptor Agonists , Isoxazoles/chemical synthesis , Phthalazines/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , Binding Sites , Biological Availability , Cell Line , Female , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Male , Maze Learning/drug effects , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Phthalazines/chemistry , Phthalazines/pharmacokinetics , Phthalazines/pharmacology , Protein Subunits/agonists , Radioligand Assay , Rats , Structure-Activity Relationship , Triazoles/pharmacokinetics , Triazoles/pharmacology , Xenopus laevisABSTRACT
Nonselective inverse agonists at the gamma-aminobutyric acid(A) (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A alpha5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , GABA-A Receptor Agonists , Nootropic Agents/chemical synthesis , Phthalazines/chemical synthesis , Triazoles/chemical synthesis , Animals , Binding, Competitive , Biological Availability , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Convulsants/chemical synthesis , Convulsants/chemistry , Convulsants/pharmacology , Dogs , Humans , Macaca mulatta , Mice , Nootropic Agents/chemistry , Nootropic Agents/pharmacology , Oocytes/metabolism , Patch-Clamp Techniques , Phthalazines/chemistry , Phthalazines/pharmacology , Radioligand Assay , Rats , Receptors, GABA-A/physiology , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology , Xenopus laevisABSTRACT
A new synthetic approach to tricyclic pyridones bearing a fused seven-membered ring is described. These compounds exhibit atropisomerism and exist in enantiomeric forms. Chiral HPLC separation of the enantiomers has allowed the rates of racemization to be measured and hence the free energy barrier for flipping the seven-membered ring to be deduced. Introduction of a further element of planar chirality leads to diastereomeric atropisomerism. The rate of interconversion of the diastereomers has been quantified by 2D EXSY NMR spectroscopy allowing a full description of the conformational dynamics of the system.
