ABSTRACT
Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compound 6, a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose.
Subject(s)
Azetidines/pharmacology , Carbamates/pharmacology , Enzyme Inhibitors/pharmacology , Monoacylglycerol Lipases/antagonists & inhibitors , Piperidines/pharmacology , Animals , Azetidines/chemistry , Azetidines/pharmacokinetics , Carbamates/chemistry , Carbamates/pharmacokinetics , Cell Line , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Mice, Inbred C57BL , Models, Molecular , Monoacylglycerol Lipases/metabolism , Piperidines/chemistry , Piperidines/pharmacokinetics , Recombinant Proteins/metabolismABSTRACT
Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.
Subject(s)
Nitriles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proteome/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrroles/pharmacology , Amino Acid Sequence , Animals , Area Under Curve , Brain/metabolism , Crystallography, X-Ray , Drug Discovery , Drug Evaluation, Preclinical , HEK293 Cells , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Mice, Inbred C57BL , Mice, Transgenic , Models, Molecular , Molecular Sequence Data , Molecular Structure , Mutation, Missense , Nitriles/chemistry , Nitriles/pharmacokinetics , Parkinson Disease/drug therapy , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , Protein Structure, Tertiary , Proteome/chemistry , Proteome/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrroles/chemistry , Pyrroles/pharmacokinetics , RatsABSTRACT
Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD). The most common mutant, G2019S, increases kinase activity, thus LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the structure, potential ligand-protein binding interactions, and pharmacological profiling of potent and highly selective kinase inhibitors based on a triazolopyridazine chemical scaffold.
