Title: The Synthesis and Preclinical Studies of New Treatments for Neurodegenerative Disease, Diabetes Mellitus, Congestive Heart Failure, Oncologic and Immunologic Disease Within the various laboratories of the National Institute on Aging (NIA), Intramural Research Program (IRP) are several lines of investigation that are not only providing insight into fundamental mechanisms of aging and age-related diseases, but also provide potential targets and agents for therapeutic intervention. This work has resulted in the identification of a number of new chemical entities, which represent lead drug candidates for the treatment of cardiovascular and neurodegenerative diseases as well as other clinical states associated with the aging process. However, there are many obstacles that must be overcome in order to translate laboratory observations into clinical realities. Once a potential lead drug candidate has been identified in the research laboratory, the development of this agent into a """"""""new drug"""""""" involves a number of necessary steps including:1)Full characterization of the interaction with the target receptor(s) and systems;2)Identification of potential """"""""off-target"""""""" interactions;3)Determination of the absorption, distribution, metabolism, excretion and toxicity of the potential drug candidate (the ADMET stage of drug discovery);4)Lead optimization involving the synthesis of a series of related compounds, the establishment of quantitative structure-activity relationships (QSAR), followed by selection of """"""""second generation"""""""" lead compounds and ADMET studies of these compounds;5)Synthesis of material for toxicology studies including the development of a """"""""good manufacturing process"""""""" synthesis of the drug candidate including proof of chemical and microbiological purity;6)Determination of the toxicology profiles of the drug candidate;7)Formulation of the drug candidate;8)Preparation of the documents required for Food and Drug Administration (FDA) approval. The studies required to accomplish these steps are routine and exacting and essentially outside of the mission and resources of the NIA research laboratories. Thus, a program was initiated to accomplish the necessary steps to develop potential new therapeutic agents up to the stage of human testing. Initially, this work was done under three (3) contracts: N01-AG-3-1008 (Preclinical Toxicology), N01-AG-3-1009(Synthesis of Lead Compounds), and N01-AG-3-1011 (Synthesis of Bulk Chemicals and Drugs for Preclinical and Clinical Studies). This program was successfully applied to the identification of (R,R')-fentoterol as a lead drug for the treatment of congestive heart failure and the steps up to the initial """"""""first-into-human"""""""" study. The program also identified a new chemical entity, meth oxyfenoterol, as a second generation agent as well as the development of a pharmacophore describing binding to the 2-adrenergic receptor. This pharmacophore lead to the synthesis of additional, highly selective agents. The present proposal is a continuation of the initial program and will include the development of meth oxyfenoterol up to the """"""""first-into-human"""""""" stage. The program will also work on the development of other possible lead drug candidates identified in the NIA laboratories including agents active in the Central Nervous System (CNS) and inflammatory diseases following the protocols developed during the first project.
