SBIR-STTR Award

The purpose of the present study is to assess the utility of muscarinic agonists in treating Alzheimer's disease. Levels of acetylcholine decrease in Alzheimer's disease, resulting in memory deficits. Efforts to treat Alzheimer's disease have been based on compounds that mimic acetylcholine without producing side effects such as salivation or diarrhea. Unfortunately, muscarinic agonists have shown limited clinical utility due to low efficacy, poor selectivity or high toxicity. Recent studies suggest however, that muscarinic agonists might be useful in treating not only memory impairments, but also the underlying causes of Alzheimer's disease. In particular, muscarinic agonists promote a-secretase activity, thereby limiting the production of b-amyloid, and stimulate Akt , which prevents the phosphorylation of tau proteins. Thus administration of efficacious, selective and safe muscarinic agonists could be beneficial in the early stages of Alzheimer's disease. 5-(3-Ethyl-1,2 4-oxadiazol-5-yl)-1 ,4,5,6-tetrahydropyrimidine (CDD-0 102) activates muscarinic receptors in brain and improves memory function with few side effects and low toxicity in the present study, CDD-01 02 will be examined for its ability to promote a-secretase and Akt activity. Metabolites of CDD-0102 will be determined and examined for receptor activity to assess safety. Together, the studies will assess the utility of CDD-01 02 in treating not only cognitive and memory deficits, but also the progression of Alzheimer's disease.

Thesaurus Terms:
Alzheimer's disease, drug design /synthesis /production, muscarine, neuropharmacologic agent acetylcholine, amyloid protein, drug metabolism, drug screening /evaluation, endopeptidase, neuropharmacology, pharmacokinetics, tau protein cell line

The purpose of this Phase II SBIR proposal is to continue the development of CDD-0102 as a potential treatment for Alzheimer's disease (AD). Accomplishments from the Phase I award included demonstration of the stimulation of alpha-secretase by CDD-0102, identification of the major metabolizing enzymes and the chemical synthesis of one potential metabolite. In AD cholinergic pathways that subserve memory degenerate, and plaques and tangles that are toxic to neurons accumulate in the brain, leading to loss of memory, behavioral disturbances, and eventually death. Existing treatments inhibit the breakdown of the transmitter acetylcholine, improving memory and behavior briefly, but do not attenuate the progression of the disease. CDD-0102 is a selective M1 receptor agonist, meaning that it binds to and activates muscarinic receptors associated with memory pathways, but not other muscarinic receptors, for example, M3 receptors that are responsible for unwanted side effects. CDD-0102 improves memory in an animal model of AD and appears to be safe based on a two-week toxicity study in rats. M1 muscarinic receptors are also linked to pathways that stimulate alpha-secretase activity, thereby preventing the formation of beta-amyloid protein that leads to plaques. The findings indicate that CDD-0102 has the potential to replace acetylcholine at M1 receptors to improve memory and reduce behavioral problems and reduce or prevent the formation of beta-amyloid and thus plaques. The studies proposed in this Phase II SBIR proposal are designed to evaluate further the potential beneficial effects of CDD-0102 and to reach the milestone of filing an Investigational New Drug application with the FDA. CDD-0102 will be synthesized for the studies, incorporating scale-up, process improvements, chemical analysis and analytical standards. Metabolites of CDD-0102 will be identified using frozen human liver cells and microsomes containing individual cytochrome P450 enzymes, as well as rats. Efficacy will be evaluated further, measuring effects on alpha-secretase. Pre-formulation of CDD-0102 will be investigated by selection of the best salt, and measurement of chemical and physical properties of different dosage forms. Additional product testing will be outsourced and performed under Good Laboratory Practice (GLP) standards by reputable firms. The proposed work will allow Cognitive Pharmaceuticals, Ltd. to reach a major milestone in the commercialization of CDD-0102 for the treatment of Alzheimer's disease.

Thesaurus Terms:
Alzheimer's disease, anticholinergic agent, brain disorder chemotherapy, drug design /synthesis /production, drug screening /evaluation, muscarine, neuropharmacologic agent, pyrimidine analog amyloid protein, analytical chemistry, chemical standardization, cholinergic receptor, cytochrome, drug interaction, drug metabolism, neuropharmacology, pharmacokinetics, receptor binding SDS polyacrylamide gel electrophoresis, calorimetry, cell line, enzyme linked immunosorbent assay, high performance liquid chromatography, laboratory rat, liquid chromatography mass spectrometry