Small molecule inhibitor of amyloid precursor protein synthesis

DESCRIPTION (provided by applicant): The product that will result from this SBIR is a small molecule drug therapy for Alzheimer's Disease (AD) that works by inhibiting amyloid precursor protein synthesis. AD accounts for two-thirds of all dementia, afflicting more than 26 million people worldwide, and in excess of 4 million Americans. The amyloid hypothesis of AD proposes that increased levels of amyloid-beta (Ab) peptides in the brain, possibly in their aggregated form, mediate a cascade of events leading to neuronal dysfunction, degeneration and clinical dementia. At present, currently approved therapies are considered to be primarily symptomatic. Although a large number of potentially disease-modifying therapeutic strategies are in current development, primarily focused on Ab and tau, the primary constituents of amyloid plaques and NFTs, respectively, none has been approved for AD treatment. [+]-Phenserine-tartrate is an experimental drug that has been exclusively licensed by QR Pharma. In both cell cultures and in animals [+]-phenserine-tartrate has been found to lower the rate of amyloid precursor protein synthesis. APP mRNA is efficiently translated and can be regulated at the level of its 5'-untranslated region (5'-UTR). [+]-phenserine-tartrate acts to lower the rate of APP synthesis via this 5'-UTR, reducing APP protein as well as Ab (1-40 and 1-42) by up to 50% in neuronal cultures and mice following both i.p. and oral administration. [+]-Phenserine-tartrate has been successfully developed through FDA required preclinical studies, has been FDA-approved for human use, and has begun Phase 1 clinical trials (single and repeated dosing). [+]- Phenserine-tartrate was well tolerated in both rodents and dogs in preclinical toxicological studies following oral administration and, likewise, was well tolerated in healthy elderly volunteers after oral dosing. A comparison of plasma concentrations achieved in humans following a well-tolerated dose with Ab-lowering concentrations in rodents suggests that effective concentrations can be achieved in humans. Collectively, these data indicate that [+]-phenserine-tartrate is an orally bioavailable small drug that readily enters the brain and can effectively lower Ab without toxicity. In all species, plasma Posiphen disappeared with a half-life of 2 to 4 hours following oral dosing, generating the major metabolite, [+]-N1,N8-bisnorposiphen, via its [+]-N1- and [+]-N8-norposiphen intermediates. These intermediates have been found to possess anticholinesterase activity, and since they achieve substantially greater concentrations than the parent drug, require to be characterized and optimized to support continued assessment of activities in the next phase of clinical studies in AD subjects. PUBLIC HEALTH RELEVANCE: The product that will result from this SBIR is a small molecule drug therapy for Alzheimer's Disease that works by inhibiting a molecular cause of the disease. Alzheimer's Disease accounts for two-thirds of all dementia. Although a number of potentially disease-modifying therapeutic strategies are in current development, none has so far been approved.