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
A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition.
Subject(s)
Aminoimidazole Carboxamide/chemical synthesis , Aminoimidazole Carboxamide/pharmacology , Janus Kinase 2/antagonists & inhibitors , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Aminoimidazole Carboxamide/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Disease Models, Animal , Enzyme Activation/drug effects , Humans , Leukemia, Myeloid, Acute/drug therapy , Microsomes/drug effects , Microsomes/enzymology , Models, Biological , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Rats , Thiophenes/chemistryABSTRACT
A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617âPhe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.
