ABSTRACT
Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aß levels in rats and nonhuman primates and CSF Aß levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Protein Precursor/antagonists & inhibitors , Cyclic S-Oxides/pharmacology , Drug Discovery , Thiadiazines/pharmacology , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Cyclic S-Oxides/chemical synthesis , Cyclic S-Oxides/chemistry , Dogs , Dose-Response Relationship, Drug , Humans , Macaca fascicularis , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiadiazines/chemical synthesis , Thiadiazines/chemistryABSTRACT
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Subject(s)
Enzyme Inhibitors/pharmacology , Imines/pharmacology , Pyrimidinones/pharmacology , Renin/antagonists & inhibitors , Administration, Oral , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Imines/chemical synthesis , Imines/chemistry , Models, Molecular , Molecular Structure , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Renin/metabolism , Structure-Activity RelationshipABSTRACT
From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aß following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Anticonvulsants/chemical synthesis , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hydantoins/chemical synthesis , Administration, Oral , Alzheimer Disease/blood , Alzheimer Disease/cerebrospinal fluid , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Anticonvulsants/pharmacology , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Computer Simulation , Crystallography, X-Ray , Disease Models, Animal , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Hydantoins/pharmacology , Models, Molecular , Protein Binding , Rats , Rats, Sprague-DawleyABSTRACT
In early 1999, beta-amyloid cleaving enzyme-1 (BACE-1) was identified as the protease responsible for the critical first step in the processing of beta-amyloid precursor protein that ultimately leads to the production of Abeta peptides in the brain. Accumulation of these peptides has been implicated in the pathology of Alzheimer's disease (AD). An inhibitor of BACE-1 would therefore have therapeutic potential to slow or halt the progression of this debilitating and ultimately fatal disease. This review provides a perspective on the recent developments in the design of BACE-1 inhibitors. An overview of early research is also included, with particular emphasis on a comprehensive survey of the patent literature.
