The goal of these studies is to determine the efficacy of proprietary geranylgeranyl diphosphate synthase inhibitors (GGSIs), for inhibition of osteoclast mediated bone resorption in comparison to current standard-of-care agents. We have developed a group of proprietary bisphosphonates containing isoprene substructures that demonstrate highly potent and specific GGSI activity in vitro. These compounds do not contain the hydroxyl group or the nitrogen substructure of the current bisphosphonates, which are used clinically. Our GGSIs represent a significant advance in bisphosphonate development in that they target a downstream enzyme relative to the clinical bisphosphonates. We feel that further development of our novel GGSIs for the treatment of osteoporosis is warranted based on the strength of our preliminary studies and the ongoing need for additional treatments for this disease which represents a significant and growing public health problem. Indeed, it is estimated that by 2025 osteoporosis will result in $25 billion worth of health costs each year. Here we propose SBIR Phase I studies to prove the feasibility of GGSIs in osteoporosis in a commonly used rat model of the disease. The feasibility studies described in this proposal provide a streamlined approach towards identification of the most active GGSI towards bone resorption from our library using in vitro models, and transition of these active compounds into an in vivo model of bone resorption. In specific aim one we will use cell based models to prioritize our compounds based on osteoclast resorption activity and inhibition of osteoblast apoptosis. Then in specific aim two we will use the highest priority compound in an ovariectomized rat model of osteoporosis and correlate the in vitro data to in vivo measurements of bone strength, biomarkers of mechanism engagement, biomarkers of bone resorption, and ex vivo markers of osteoblast apoptosis. Together these aims will provide us with a go or no-go decision for more elaborate IND enabling studies.
Public Health Relevance Statement: Public Health Relevance: The International Osteoporosis Foundation (IOF) estimates that in 2009 there were approximately 75 million people affected by osteoporosis in the U.S., Europe, and Japan (www.iofbonehealth.org). While much progress has been made in detection and treatment of osteoporosis, bone fractures remain a significant barrier to quality of life and overall survival. In this proposal we advocate developing drugs based on inhibiting an unexploited biological process (protein geranylgeranylation) that is known to be important to processes in osteoporosis including osteoclast-mediated bone resorption. Development of new targeted therapies for bone resorption could have a great impact on this patient population.
NIH Spending Category: Aging; Osteoporosis
Project Terms: Advanced Development; Advocate; Affect; Affinity; Anabolism; Apoptosis; base; Binding (Molecular Function); Biological Markers; Biological Process; bisphosphonate; bone; Bone Matrix; Bone necrosis; Bone remodeling; Bone Resorption; bone strength; bone turnover; Calcium; Caring; cathepsin K; Cell Line; Cells; Characteristics; Clinical; clinical application; Cultured Cells; Cyclophosphamide; Data; Detection; Development; Disease; Disease model; Drug Kinetics; Enzymes; Europe; farnesyltranstransferase; Feasibility Studies; Foundations; Fracture; Functional disorder; Funding; geranylgeranyl diphosphate; Goals; Health Care Costs; Human; hydroxyl group; In Vitro; in vitro activity; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; International; Intervention; Isoprene; isoprenoid; Japan; Jaw; Kidney; Lead; Libraries; Measurement; Measures; Mechanical Stress; Mechanics; Mediating; Metabolism; Modality; Modeling; New Agents; Nitrogen; novel; Osteoblasts; Osteocalcin; Osteoclasts; Osteocytes; Osteoporosis; Pathway interactions; patient population; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; pharmacophore; Phase; phase 1 study; phase 2 study; Population; Prevalence; Process; Production; programs; Protein Geranylgeranylation; public health medicine (field); public health relevance; Quality of life; Rattus; Regulation; Relative (related person); Resistance; Series; skeletal; Small Business Innovation Research Grant; small molecule; small molecule libraries; Solutions; spine bone structure; standard care; Supplementation; Testing; Therapeutic; Toxic effect; TRANCE protein; Vitamin D
