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

Abstract

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
URI:	https://oak.novartis.com/id/eprint/8539