ABSTRACT
The initial structure activity relationships around an isoindoline uHTS hit will be described. Information gleaned from ligand co-crystal structures allowed for rapid refinements in both MARK potency and kinase selectivity. These efforts allowed for the identification of a compound with properties suitable for use as an in vitro tool compound for validation studies on MARK as a viable target for Alzheimer's disease.
Subject(s)
Drug Design , Protein Kinase Inhibitors/pharmacology , Pyrimidinones/pharmacology , Pyrroles/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Cell Line , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer's disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro-in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.
Subject(s)
Alzheimer Disease/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrimidinones/pharmacology , Pyrroles/pharmacology , Alzheimer Disease/metabolism , Animals , Dose-Response Relationship, Drug , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Pyrimidinones/chemistry , Pyrimidinones/metabolism , Pyrroles/chemistry , Pyrroles/metabolism , Rats , Structure-Activity RelationshipABSTRACT
[reaction: see text] A synthesis of a pectenotoxin 4 C1-C15 segment is reported. Suitable C1-C7 and C8-C15 segments were prepared, coupled, converted to I and the C3-hydroxy variant, and then cyclized. Key findings include the stereoselective conversion of the allene to the corresponding spirodiepoxide, oxidative cleavage of the p-methoxybenzyl ether, and cyclization of the spirodiepoxide to spiroketal II.
