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The Chemistry of Bisphosphonates: From anti-scaling agents to potent therapeutics

Widler, Leo and Green, Jonathan (2012) The Chemistry of Bisphosphonates: From anti-scaling agents to potent therapeutics. Anti-cancer Agents in Medicinal Chemistry, 12 (2). pp. 95-101. ISSN PMID:21864230


In the early 1960s inorganic pyrophosphate (PPi) was found to be present in body fluids and to act as a natural inhibitor of calcification by its interaction with hydroxyapatite. In addition to inhibiting the formation of calcium phosphate, PPi also inhibited dissolution of hydroxyapatite crystals which made it interesting for pharmalogical applications in the treatment of diseases associated with excessive bone resorption. However, pyrophosphate is metabolically unstable because of rapid hydrolysis of the P-O-P backbone by hydrolytic enzymes in the gastrointestinal tract. In the search for more stable analogues of PPi, attention turned to the chemical class of bisphosphonates (BPs). The first BPs were synthesized in the 19th century and have been widely used for industrial applications. Bisphosphonates are formally derived from pyrophosphate by replacement of the bridging oxygen atom by a carbon atom resulting in a P-C-P moiety which is resistant to enzymatic hydrolysis. In addition to its decisive role in stability, the central carbon atom also provides an attachment point for two additional substituents R1 and R2. While R1 is preferentially a hydroxy group, allowing such derivatives to act as powerful tridentate ligands for calcium (bone hook), R2 is mainly responsible for anti-resorptive potency. The clinically available BPs can be divided into 2 subclasses based on their structure and molecular mechanism of action. The simple, non-nitrogen containing derivatives can be incorporated into non-hydrolysable cytotoxic ATP analogues. The more potent nitrogen-containing BPs inhibit FPPS, a key enzyme in the mevalonic pathway. Members of this class have a wide therapeutic window between undesired inhibition of bone formation and bone resorption and several of them have found widespread use for the treatment of benign and malignant bone disease.

Item Type: Article
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Additional Information: review article; all Novartis data and compounds have previously been published (J. Med. Chem. 2002, 45, 3721)
Keywords: bisphosphonic acid; osteoporosis; resorption inhibitor, FPPS inhibitor
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15