Close to 60 matrix metalloproteinase (MMP) inhibitors have been pursued as clinical candidates since the first drug discovery program targeting this enzyme family began in the late seventies. Targeted indications included cancer, arthritis, cardiovascular diseases, and many others. However, the clinical development of most of the MMP inhibitors have been discontinued due to safety reasons and so far only Periostat (doxycycline hyclate, a nonspecific MMP inhibitor) has been approved for periodontal disease. Because of the high therapeutic potential, the development of MMP inhibitors continues as shown by several recent patents and scientific publications. Development of selective MMP inhibitors lacking serious side-effects such as musculoskeletal syndrome is of high importance. Innovative approaches for the design of selective MMP inhibitors include the integration of classical medicinal chemistry structure-based properties and design features into the emerging chemogenomics concept of target-family based drug discovery. This approach, which includes privileged structures, molecular frameworks, bioisosteric and bioanalogous/isofunctional modifications (the “matrixinome” approach), may lead to highly selective MMP inhibitors in the future.
Keywords: Matrix metalloproteinase, MMP, inhibitors, selectivity, safety, efficacy, heart failure, remodelling, infarction
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