Our lab has designed and characterized a "first in class" novel small-molecule drug (i.e. Cmpd-3) that improves learning and memory in Alzheimer's Disease (AD) mice with reduced AD biomarker profile and does so by increasing the ability to form memories and to protect and increase the number of neurons in the brain. We have an extensive pharmacological profile of Cmpd-3 and a derivative (i.e. Cmpd-14) which demonstrates high selectivity for the receptor target, and selective signaling-bias that would enhance the cognitive benefits but minimize or eliminate potential cardiovascular side effects, such as increased blood pressure. We have shown that Cmpd-3 can fully reverse memory deficits in two genetically different AD mouse models, established a range of effective doses in these mice, and evidenced a safe drug profile. In addition, Cmpd-3 can fully reverse AD biomarkers in the plasma of the AD mouse model, something which Aricept  (the current drug of choice for AD) could not do. Our goal in this grant proposal is to begin IND-enabling studies to further de-risk Cmpd-3.