ABSTRACT
N-methyl-D-aspartate receptor (NMDAR)-positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington's disease (HD) and Alzheimer's disease. Dalzanemdor (SAGE-718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first-in-human, phase I, double-blind, dose-finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single-ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple-ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open-label dalzanemdor 1.0 mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once-daily dosing. Following single and multiple doses in healthy participants, median terminal half-life was 8-118 h, and the median time to reach maximum plasma concentration was 4-7 h. Exposures were dose-proportional after single dose (6-46 ng/mL) and more than dose-proportional after multiple doses (6-41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction.
Subject(s)
Dose-Response Relationship, Drug , Huntington Disease , Receptors, N-Methyl-D-Aspartate , Humans , Male , Adult , Huntington Disease/drug therapy , Female , Middle Aged , Double-Blind Method , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Allosteric Regulation/drug effects , Young Adult , Healthy Volunteers , Adolescent , Cognition/drug effects , AgedABSTRACT
Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12.
Subject(s)
Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Drug Discovery , Indoles/pharmacology , Receptors, CCR/antagonists & inhibitors , Colitis, Ulcerative/metabolism , Crohn Disease/metabolism , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Receptors, CCR/metabolism , Structure-Activity RelationshipABSTRACT
Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, affects millions of people worldwide. CCR9 has been shown to be a key chemokine receptor mediating the local inflammatory responses in the GI tract. The CCR9 inhibitor Vercirnon advanced to phase 3 clinical trials, but carries several liabilities which we sought to improve.
Subject(s)
Inflammatory Bowel Diseases/drug therapy , Receptors, CCR/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Chemistry Techniques, Synthetic , Drug Evaluation, Preclinical/methods , Humans , Inhibitory Concentration 50 , Mice , Structure-Activity RelationshipABSTRACT
Daptomycin (DAP) is a cyclic lipopeptide antibiotic used for the treatment of certain Staphylococcus aureus infections. Although rare, strains have been isolated that are DAP resistant. These strains usually have mutations in mprF, a gene encoding a membrane protein with both lysylphosphatidylglycerol (LPG) synthase and flippase activities. Because ΔmprF strains have increased DAP susceptibility, the mechanism of resistance is not likely due to a loss of mprF function. In this study, we developed an LC-MS assay to examine the effect of different mprF mutations on the ratio of phosphatidylglycerol (PG) to LPG in the membrane. Our assay demonstrated that some, but not all, mutations in the flippase and synthase domains result in small but reproducible increases in the proportion of LPG relative to PG. Techniques described herein represent a higher throughput and more sensitive method for measuring relative phospholipids levels. These results offer guidance in the understanding of how mprF confers DAP resistance; namely, mprF-mediated resistance may be through more than one mechanism, including increased overall LPG synthesis and increased LPG present on the outer leaflet of the cytoplasmic membrane.
Subject(s)
Aminoacyltransferases/genetics , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , Daptomycin/pharmacology , Mutation , Phospholipids/chemistry , Staphylococcus aureus/drug effects , Staphylococcus aureus/genetics , Chromatography, Liquid , Ions/chemistry , Lysine/analysis , Lysine/chemistry , Microbial Sensitivity Tests , Phosphatidylglycerols/analysis , Phosphatidylglycerols/chemistry , Phospholipids/analysis , Staphylococcus aureus/chemistry , Tandem Mass SpectrometryABSTRACT
The introduction of novel, powerful and rapid multidimensional separation and characterization methods has produced revolutionary global changes at the genome, proteome and metabolome level, bringing about a radical transition in our views of living systems, at the molecular level. The age of proteomics and metabolomics demands high-resolution multidimensional separation techniques. Multidimensional gas and liquid chromatography techniques, in addition to capillary and microchip electrophoresis methods, offer increased resolution and sensitivity, while also affording adequate throughput and reproducibility to meet the demands of the modern pharmaceutical industry. Coupled with MS, these techniques provide not only separation but also reliable identification of the sample components. The resolving power of these methods has proved to be superior over individual one-dimensional approaches, enabling the comprehensive separation of complex biological mixtures, with excellent resolution and reproducibility. High capacity computer systems that are capable of rigorous qualitative and quantitative analysis of the separation profiles allow the establishment and mining of large databases. Examples of various modern multidimensional separation techniques, and their integration with MS, are reviewed, here, with respect to pharmaceutical analysis.