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A General Strategy for Targeting Drugs to Bone

Jahnke, Wolfgang, Bold, Guido, Marzinzik, Andreas, Ofner, Silvio, Pelle, Xavier, Cotesta, Simona, Bourgier, Emmanuelle, Lehmann, Sylvie, Henry, Christelle, Hemmig, Rene, Green, Jonathan and Rondeau, Jean-Michel (2015) A General Strategy for Targeting Drugs to Bone. Angewandte Chemie Int Edition, 54 (48). pp. 14575-14579. ISSN 14337851


We recently described allosteric, non-bisphosphonate inhibitors of FPPS which lack affinity to bone, and can thus be explored for their anti-tumor and cholesterol-lowering potential. Another novel and promising avenue opened up by the discovery of these allosteric FPPS inhibitors comprises the design of non-bisphosphonate FPPS inhibitors which display affinity to bone, but to a much lesser extent compared to N-BPs. Such compounds could potentially become better drugs for the treatment of bone diseases as they may display an improved oral bioavailability, a more even distribution throughout the skeleton, and a faster elimination time than the currently available N-BP drugs, which have a very low oral absorption and are very slowly released from the skeleton.
Here we report the attachment of a monophosphonate functionality to allosteric inhibitors of FPPS. Taking advantage of our NMR-based bone binding assay, we show that, in sharp contrast to N-BPs, the bone affinity of these compounds can be tuned to the desired degree, independently from their inhibitory potency towards FPPS. Targeting a drug to the diseased tissue or organ is an attractive concept for improving efficacy and reducing adverse effects. The work described here provides a practical approach to confering a suitable degree of bone affinity to a drug candidate, and may therefore become a general strategy to improve the safety and efficacy of drugs acting on bone

Item Type: Article
Additional Information: The manuscript together with the IP inventory has been sent to the GDC leadership team on August 13, 2012. GDC has no objections to the publication.
Keywords: FPPS fragment-based screening allosteric inhibitor bone-affinity tag
Date Deposited: 12 May 2016 23:45
Last Modified: 04 Jul 2016 23:46


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