This proposal originates from data obtained under grant R21 NS45327 entitled Compound Identification in Assays for Tau Pathology. With those funds we established a high throughput screen and discovered novel compounds that inhibit Cdk5. The in vitro screen detects compounds that inhibit the phosphorylation of recombinant full-length tau by purified Cdk5 performed in the presence of high amounts of ATP. This strategy was designed to obtain 'hits' that do not bind to the ATP pocket of the kinase, and therefore differ from the known Cdk5 inhibitors. From an initial screen of 58,000 drug-like compounds, we have three lead compounds with single digit or sub-micromolar ICso's and with distinct mechanisms of action. One compound is competitive with ATP and has a high affinity for the Cdk5 ATP-binding pocket. The second compound also competes with ATP, is non-competitive with tau, and uniquely among this class of inhibitors, displaces adjacent amino acid residues to make room for the nitrophenyl group. Most importantly for our strategy was the third compound, which did not compete with ATP, but did compete with tau, and therefore may prove to be more specific than compounds which bind the conserved ATP pocket. Indeed, this compound has an approximately three-fold lower IC50 for Cdk5 than for GSK3P and an approximately six-fold lower IC5o for Cdk5 than for Cdc2. We propose to increase the number of lead compounds to twenty by screening additional libraries for in vitro IC50<100 nM, and with EC50<1 mM and LD50>100 mM in cell based and in vivo assays. To enhance the likelihood of finding compounds that do not compete with ATP we have modified our screening strategy and our preliminary data supports the idea that such compounds can be detected. Based on ranking of several factors including chemical tractability, toxicology, pharmacokinetics, and some ADME, five compounds will be selected for chemical modification. The optimized compounds from each of the five series will'be assessed for efficacy in animal models of neurofibrillary pathology developed within our collaborative group. From these data we will select one or two compounds for complete safety pharmacology. By the end of Year 5 we will apply for an Investigation of New Drug (IND) to the Food and Drug Administration (FDA) for a human phase I clinical trial to treat frontotemporal dementia. Because compound validation requires a broad expertise that is unlikely to be present in a single lab we have assembled individuals who collectively have the expertise to complete the aims.