Optimization and Lead Selection of an Iminosugar Pharmacological Chaperone for the Treatment of Alzheimer's Disease

DESCRIPTION provided by applicant Currently there are more than million people living with Alzheimerandapos s disease AD in the United States and this number is projected to nearly triple by with annual costs of long term care expected to exceed $ trillion Alzheimerandapos s disease AD is the most common form of dementia among the elderly resulting from progressive memory loss associated with the aberrant accumulation of amyloid beta A in the brain and cerebrovasculature over the course of multiple decades While genetic evidence clearly implicates the A pathway in Alzheimerandapos s disease secretase and secretase inhibitors appear to have on target toxicities and A immunotherapies have not demonstrated clinical efficacy in phase human trials OrPhiandapos s approach acts upstream of the immunotherapies by preventing the formation of toxic A oligomers inside neurons without altering normal A processing and function OrPhi Therapeutics has demonstrated proof of concept in a novel A oligomer Alzheimerandapos s disease model APPE Q using a pharmacological chaperone OT designed to decrease ganglioside bound A Pharmacological chaperone OT has good drug like properties including good potency high target selectivity low cytotoxicity and good oral bioavailability and plasma PK characteristics Blood brain barrier BBB penetration is acceptable however there is an opportunity for enhancement of BBB penetration providing a means to lower the effective dose of our candidate molecule This grant application proposes a rationally designed highly focused medicinal chemistry effort followed by in vitro and in vivo assessment of various pharmacological properties These assessments include in vitro target binding affinity selectivity cell based enhancement properties general cell toxicit metabolic stability cardiotoxicity genotoxicity BBB penetration brain PK and oral bioavailability Quantitative criteria have been established for culling OT and OT analogues At the conclusion of the project OT and non culled analogues will be ranked according to lowest predicted effective dose and a lead candidate will be selected PUBLIC HEALTH RELEVANCE The fact that there are no therapies to prevent or slow the progression of Alzheimerandapos s disease AD and currently more than million Americans living with AD presents a daunting economic and social challenge for the United States The present proposal supports the optimization and selection of a small molecule to be used in an innovative pharmacological chaperone therapy targeting a novel ganglioside A reducing mechanism of action for the treatment of AD