Target validation and lead identification for the development of disease modifying drugs in osteoarthritis (OA)

Osteoarthritis affects approximately 60% of over 65 year olds causing pain, joint stiffness and poor mobility which often reduce independence and quality of life in sufferers. It is caused by gradual degradation of cartilage and bone within the affected joints. The most common joints affected are the knee and hip and a significant proportion of knee replacements are due to osteoarthritis. The current treatments are pain killers, anti-inflammatory drugs and corticosteroids which do not prevent or slow the progression of the disease, have side effects and at best only relieve the symptoms of osteoarthritis. An effective ?disease-modifying osteoarthritis drug? would target a detrimental protein present in the osteoarthritic joint but not the normal joint. Our research has identified such a protein, an enzyme which promotes cartilage degradation. Drugs designed to stop this enzyme will prevent further joint damage. In this project, the first stages of design and testing a drug to block this enzyme will be completed.
The impact of a drug treatment for osteoarthritis in patients would be reduced symptoms, improved quality of life, and reduced need for joint replacement surgery. This would mean reduced costs for patient care for the NHS and healthcare providers. The development of an effective drug for osteoarthritis would have a large commercial value to the pharmaceutical industry.

There is an urgent, growing, unmet need for OA disease modifying osteoarthritis drugs (DMOADs) as the incidence of OA is rising in an ageing and increasingly obese population. This project aims to deliver one or more novel LEAD COMPOUNDS as DMOADs. Osteoarthritis (OA) is the most common degenerative joint disease in the elderly, causing arthritis in over 70million people worldwide. Analgesics and joint replacement surgery are the only current treatment options. We have identified an OA specific enzyme which is expressed only in the OA joint following trauma or repetitive stress injury. The enzyme is an ideal target for an inhibitory drug as it initiates degradation in OA, but not normal, cartilage and is not expressed in the normal adult. It directly activates matrix metalloproteinases (MMPs), enzymes which are critical for cartilage destruction, via a receptor known to be elevated in OA and linked to pain. Effective enzyme inhibition will stop cartilage breakdown and reduce joint pain.
Target validation will be confirmed in an established OA model using enzyme specific inhibitors (developed for cancer and provided by collaborators) and with a novel transgenic mouse. Novel lead compounds for OA will be generated using all known inhibitors and computational medicinal chemistry and selected by screening in OA models. This solution will slow OA progression and so mitigate health and social costs and improve quality of life for patients.