Discovery and Development of the Immunomodulatory Azaspiranes

Abstract

The search for new agents for the therapy of autoimmune diseases and transplantation is a continuous and often frustrating task. For rheumatoid arthritis (RA), a chronic inflammatory immune-mediated disease, that leads to severe damage of the articular cartilage and subchondral bone, there is no one agent or combination of agents fully capable of stopping disease progression or reversing the damage. First line therapy consists of nonsteroidal anti-inflammatory drugs (NSAIDs). This is followed by the use of disease-modifying antirheumatic drugs (DMARDs), also called slow acting antirheumatic drugs (SAARDs), whose mechanisms of action are not well defined. Some DMARDs are currently used because of clinical observations made during treatment of other diseases (Kavanaugh and Lipsky, 1992). For example, gold compounds which were initially used for the treatment of tuberculosis, were introduced for rheumatoid arthritis due to certain similarities between the two diseases and the belief that they might both be caused by a mycobacterium. An improvement in arthritic lesions in malaria patients treated with mepacrine prompted clinical trials with chloroquine and hydroxychloroquine. D-penicillamine, first used in the treatment of Wilson’s disease, was found to cause dissociation of macroglobulins, including IgM rheumatoid factor in vitro and formed the basis for its use in RA.