Grant: Collaborative Health Research Projects (NSERC partnered)

Bisphosphonates are a class of drugs used to treat metabolic bone disorders such as hypercalcemia, Paget's disease and, in oral form, for the treatment of postmenopausal osteoporosis. Due to their poor lipophilicity and polarity they possess very low bioavailability, typically less than 1%. Two recent (2008, 2010) case studies have suggested a link between prolonged bisphosphonate therapy and atypical fractures. It is evident that though effective, due to their adverse side effects, cost, and low patient compliance, more effective medications are necessary for the treatment of postmenopausal osteoporosis. The chemical elements the lanthanides (Ln) share many similar biomolecular binding attributes with calcium, Ca, including a high affinity for the bone matrix; Ln(III) also share with Ca(II) similar ionic radii, donor atom preferences, and almost identical coordination numbers in protein binding sites. Our hypothesis is that chemical compounds of the lanthanide elements with designed ligands have potential as therapeutic agents for bone disorders in humans; bone disorders in which the bone remodeling cycle is disrupted include osteoporosis, osteomalacia, osteoarthritis and periodontal disease. In preliminary published work (Dalton Trans. 2007), we identified one preliminary lead compound (La(dpp)3) based on preliminary in vitro and cell studies. The proposal concerns the design, synthesis, characterization and testing of a series of lanthanide compounds with ligands of varying lipophilicity. Our goal is to translate the results of our early stage lanthanide hydroxypyridinone discovery into drug candidates for the treatment of a number of bone density disorders. By incorporating phosphorylated substituents into some ligand candidates, so they can bind to both bone and lanthanides, it is possible that an active agent may also be discovered which works in the absence of an added lanthanide, diversifying the design paradigm. Two lead compounds of interest are expected to result from this work, at the conclusion of which we should be ready for advanced preclinical and early human studies. As the Canadian population ages, more and better drugs for such aging conditions as osteoporosis are required.