Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy.
|Abstract||The bisphosphonates (BPs) are well established as the treatments of choice for disorders of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. There is considerable new knowledge about how BPs work. Their classical pharmacological effects appear to result from two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. Mineral binding affinities differ ... [truncated at 450 characters in length]|
|Author||Russell, R Graham G; Xia, Zhidao; Dunford, James E; et al|
|Subject||Animals Bone Neoplasms Bone Resorption Bone and Bones Diphosphonates Guanosine Triphosphate Humans Models, Biological Models, Chemical Multiple Myeloma Neoplasm Metastasis Nitrogen Osteoclasts Osteocytes Osteoporosis Protein Processing, Post-Translational T-Lymphocytes Treatment Outcome secondary metabolism chemistry pharmacology therapeutic use chemistry metabolism chemistry metabolism metabolism therapy metabolism|
Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase.
|Abstract||The nitrogen-containing bisphosphonates (N-BPs) are the main drugs currently used to treat diseases characterized by excessive bone resorption. The major molecular target of N-BPs is farnesylpyrophosphate synthase. N-BPs inhibit the enzyme by a mechanism that involves time dependent isomerization of the enzyme. We investigated features of N-BPs that confer maximal slow and tight-binding by quantifying the initial and final K(i)s and calculating t ... [truncated at 450 characters in length]|
|Author||Dunford, James E; Kwaasi, Aaron A; Rogers, Michael J; et al|
|Subject||Binding Sites Diphosphonates Enzyme Inhibitors Geranyltranstransferase Humans Models, Molecular Molecular Structure Nitrogen Stereoisomerism Structure-Activity Relationship Time Factors chemistry pharmacology chemistry pharmacology antagonists and inhibitors chemistry|
Targeting a uniquely nonspecific prenyl synthase with bisphosphonates to combat cryptosporidiosis.
|Abstract||Cryptosporidiosis is a neglected disease without a wholly effective drug. We present a study demonstrating nitrogen-containing bisphosphonates (N-BPs) to be capable of inhibiting Cryptosporidium parvum at low micromolar concentrations in infected MDCK cells. Predictably, the mechanism of action is based on inhibition of biosynthesis of isoprenoids but the target enzyme is unexpectedly a distinctive C. parvum enzyme dubbed nonspecific polyprenyl p ... [truncated at 450 characters in length]|
|Author||Artz, Jennifer D; Dunford, James E; Arrowood, Michael J; et al|
|Subject||Animals Anti-Infective Agents Cattle Cells, Cultured Chromatography, Liquid Cryptosporidiosis Cryptosporidium parvum Crystallography, X-Ray Dimethylallyltranstransferase Diphosphonates Fluorescent Antibody Technique Humans Inhibitory Concentration 50 Models, Molecular Molecular Structure Protein Prenylation therapeutic use drug therapy drug effects enzymology antagonists and inhibitors metabolism pharmacology therapeutic use|