odanacatib and relacatib

We should consider not only controlling disease activity using DMARDs and biologics as a matter of course, but also preventing against joint destruction, in the treatment for rheumatoid arthritis. Although we can indirectly regulate bone erosion via controlling disease activity, the osteoclast-targeting therapy might be more effective to stop joint destruction. We are waiting for new drugs directly targeting osteoclasts, such as OPG which is the natural inhibitor of RANKL, or cathepsin K inhibitor which reduces degeneration of bone matrix.

Topics: Animals; Arthritis, Rheumatoid; Azepines; Biphenyl Compounds; Cathepsin K; Cathepsins; Cell Differentiation; Drug Design; Humans; Joints; Osteoclasts; Osteoprotegerin; Pyridines; RANK Ligand; Sulfones

Cancer cells that metastasize to the skeleton are, on their own, rarely able to destroy bone. Instead, they stimulate the function of bone-degrading cells, the osteoclasts, leading to the formation of osteolytic lesions. The purpose of this review is to consider cathepsin K, a cysteine protease produced by osteoclasts, as a therapeutic target for the treatment of patients with osteolytic bone metastases.. Cathepsin K plays a key role in osteoclast-mediated bone degradation. It is also produced by cancer cells that metastasize to bone where it functions in proteolytic pathways that promote cancer cell invasion. Highly selective and potent cathepsin K inhibitors have been recently developed and shown to be useful antiresorptive agents to treat osteoporosis. Moreover, preclinical studies show that cathepsin K inhibitors reduce breast cancer-induced osteolysis and skeletal tumor burden. This reduction of skeletal tumor burden is due to the antiresorptive activity of cathepsin K inhibitors, which in turn, deprive cancer cells of bone-derived growth factors that are required for tumor growth.. Cathepsin K inhibitors are appropriate drugs to treat diseases associated with increased bone loss. However, their chronic use in treating osteoporosis may result in adverse effects because basic nitrogen-containing cathepsin K inhibitors accumulate within acidic organelles such as lysosomes, thereby inhibiting the activity of other cathepsins. These adverse effects should not, however, preclude the use of these drugs in life-threatening diseases such as bone metastasis.

Topics: Azepines; Benzamides; Biphenyl Compounds; Bone Neoplasms; Bone Remodeling; Bone Resorption; Breast Neoplasms; Cathepsin K; Cathepsins; Female; Humans; Male; Osteoclasts; Piperazines; Prostatic Neoplasms; Sulfones; Thiazoles

Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.

Topics: Animals; Azepines; Biphenyl Compounds; Cathepsin K; Cathepsins; Collagen; Cysteine Proteinase Inhibitors; Dogs; Fibroblasts; Humans; Models, Biological; Molecular Structure; Osteoporosis, Postmenopausal; Skin; Structure-Activity Relationship; Sulfones