2020
A promising series of pyridazine-derived gamma-secretase modulators (GSMs) has been discovered in our labs at the University of California, San Diego, and Massachusetts General Hospital that inhibit the formation of the aggregation-prone amyloid beta-42 peptide in favor of shorter, less pathogenic amyloid beta isoforms. Comprehensive ADMET profiling, pharmacokinetic and pharmacodynamic studies of these promising compounds, funded by a U01 grant from the National Institutes of Health, identified compound 3 (776890) as an ideal candidate for clinical development. As part of the development of compound 3, a chronic treatment (three-month) efficacy study was conducted using 3-month-old and 6-month-old transgenic APP/PS1 mice to evaluate the effect of compound 3 on amyloid beta plaque accumulation, as well as to assess the long-term safety and tolerability of the compound. Measurement of amyloid levels showed chronic administration of compound 3 at 25 mg/kg for three months led to robust decreases in soluble and insoluble forms of amyloid beta-42 in both groups. Further histochemical analysis of the brain tissue samples from these chronic studies is proposed in order to ascertain the impact of treatment on neuritic plaques and inflammatory biomarkers, as well as to quantify the drug levels present in treated animals. Completion of these analyses will provide critical pharmacodynamics data allowing the assembly and submission of a comprehensive pre-IND briefing document required for the impending pre-IND meeting with the U.S. Food and Drug Administration prior to IND filing. These critical biological data ultimately will support the mechanistic aspects of the NDA and not the IND for phase I studies, which are strictly concerned with safety and toxicity aspects, and not efficacy.
Steven L. Wagner, Ph.D.
