A General Strategy for Targeting Drugs to Bone. Issue 48 (12th October 2015)

• Record Type: Journal Article
• Authors: Jahnke, Wolfgang; Bold, Guido; Marzinzik, Andreas L.; Ofner, Silvio; Pellé, Xavier; Cotesta, Simona; Bourgier, Emmanuelle; Lehmann, Sylvie; Henry, Chrystelle; Hemmig, René; Stauffer, Frédéric; Hartwieg, J. Constanze D.; Green, Jonathan R.; Rondeau, Jean‐Michel
• Is Part Of: Angewandte Chemie international edition. Volume 54:Issue 48(2015)
• Page Start: 14575
• Page End: 14579
• Publication Date: 2015-10-12
• Subjects: AMP397 (becampanel) -- bone‐affinity tag -- drug delivery -- NMR spectroscopy -- tissue targeting; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201507064
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Targeting drugs to their desired site of action can increase their safety and efficacy. Bisphosphonates are prototypical examples of drugs targeted to bone. However, bisphosphonate bone affinity is often considered too strong and cannot be significantly modulated without losing activity on the enzymatic target, farnesyl pyrophosphate synthase (FPPS). Furthermore, bisphosphonate bone affinity comes at the expense of very low and variable oral bioavailability. FPPS inhibitors were developed with a monophosphonate as a bone‐affinity tag that confers moderate affinity to bone, which can furthermore be tuned to the desired level, and the relationship between structure and bone affinity was evaluated by using an NMR‐based bone‐binding assay. The concept of targeting drugs to bone with moderate affinity, while retaining oral bioavailability, has broad application to a variety of other bone‐targeted drugs. Abstract : To the bone : Drugs for bone diseases benefit from targeting to bone. Bone‐affinity tags are presented that can be attached to bone‐acting drug molecules to make them safer and more efficacious, while retaining desired properties such as cellular permeability and oral bioavailability. This was demonstrated for allosteric inhibitors of farnesyl pyrophosphate synthase.