ABSTRACT
The α7 nicotinic acetylcholine receptor is a calcium permeable, ligand-gated ion channel that modulates synaptic transmission in the hippocampus, thalamus, and cerebral cortex. Previously disclosed work described PNU-120596 that acts as a powerful positive allosteric modulator of the α7 nicotinic acetylcholine receptor. The initial structure-activity relationships around PNU-120596 were gleaned from screening a large thiazole library. Independent systematic examination of the aryl and heteroaryl groups resulted in compounds with enhanced potency and improved physico-chemical properties culminating in the identification of 16 (PHA-758454). In the presence of acetylcholine, 16 enhanced evoked currents in rat hippocampal neurons. In a rat model of impaired sensory gating, treatment with 16 led to a reversal of the gating deficit in a dose-dependent manner. These results demonstrate that aryl heteroaryl ureas, like compound 16, may be useful tools for continued exploration of the unique biology of the α7 nicotinic acetylcholine receptor.
Subject(s)
Receptors, Nicotinic , alpha7 Nicotinic Acetylcholine Receptor , Rats , Animals , Hippocampus , Phenylurea Compounds/chemistry , Isoxazoles/pharmacology , Isoxazoles/chemistry , Allosteric RegulationABSTRACT
The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported.
Subject(s)
JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Mitogen-Activated Protein Kinase 8/antagonists & inhibitors , Mitogen-Activated Protein Kinase 8/metabolism , Structure-Activity RelationshipABSTRACT
A series of pyridine ether PPAR agonists were synthesized through an ADDP and PS-PPh3 modified Mitsunobu protocol, which eliminated significant by-product formation. This method proved to be versatile, efficient and amenable to parallel synthesis.
ABSTRACT
A series of novel pyridine-3-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compounds (S)-14 and (S)-19 were selected for further profiling.
