ABSTRACT
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement.
Subject(s)
Cognition/drug effects , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Animals , Dogs , Nicotinic Agonists/chemistry , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A series of α7 nicotinic acetylcholine receptor full agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Early lead 1 was found to have a limited therapeutic index with respect to its potential for cardiovascular side effects. Further optimisation of this series led to the identification of 22 a potent full agonist showing efficacy at a dose of 0.1mg/kg in the novel object recognition model of cognition enhancement. Comparison of 1 with 22 demonstrated the latter to have an improved oral pharmacokinetic profile and cardiovascular therapeutic index.
Subject(s)
Cognition/drug effects , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Animals , Dose-Response Relationship, Drug , Rabbits , Receptors, Nicotinic/chemistry , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists.
Subject(s)
Chemistry, Pharmaceutical/methods , Ghrelin/chemistry , Receptors, Ghrelin/antagonists & inhibitors , Sulfones/chemistry , Administration, Oral , Animals , Biological Availability , Drug Design , Growth Hormone/chemistry , Male , Models, Chemical , Protein Processing, Post-Translational , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/chemistry , Structure-Activity RelationshipABSTRACT
A series of pyridone-N-benzyl-propanoic acids have been optimised to afford potent orally bioavailable VLA-4 antagonists.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Pyridones/pharmacology , Administration, Oral , Animals , Pyridones/administration & dosage , Pyridones/pharmacokinetics , RatsABSTRACT
A novel series of pyridone inhibitors has been identified through pharmacophore analysis, as potent antagonists of VLA-4.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Pyridones/chemical synthesis , Pyridones/pharmacology , Binding Sites , Drug Design , Structure-Activity Relationship , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
A novel series of 6-aryl-pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyridines/chemical synthesis , Animals , Binding Sites , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Pyridines/pharmacology , Structure-Activity Relationship , WaterABSTRACT
A series of 6-heteroaryl-pyrazolo[3,4-b]pyridines has been optimised to afford potent inhibitors of Glycogen Synthase Kinase-3 (GSK-3). These analogues display excellent selectivity over the closely related Cyclin Dependent Kinase-2 (CDK-2).
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyridines/chemical synthesis , Animals , CDC2-CDC28 Kinases/antagonists & inhibitors , Cyclin-Dependent Kinase 2 , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
A novel series of pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Glycogen Synthase Kinase 3/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography.