ABSTRACT
Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Crystallography, X-Ray , Dogs , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Weight , Rats , SolubilityABSTRACT
A stereoselective nickel-catalyzed [2+2] cycloaddition of ene-allenes is reported. This transformation encompasses a broad range of ene-allene substrates, thus providing efficient access to fused cyclobutanes from easily accessed π-components. A simple and inexpensive first-row catalytic system comprised of [Ni(cod)2 ] and dppf was used in this process, thus constituting an attractive approach to synthetically challenging cyclobutane frameworks under mild reaction conditions.
