1185351-07-8Relevant academic research and scientific papers
Discovery of novel allosteric non-bisphosphonate inhibitors of farnesyl pyrophosphate synthase by integrated lead finding
Marzinzik, Andreas L.,Amstutz, René,Bold, Guido,Bourgier, Emmanuelle,Cotesta, Simona,Glickman, J. Fraser,G?tte, Marjo,Henry, Christelle,Lehmann, Sylvie,Hartwieg, J. Constanze D.,Ofner, Silvio,Pellé, Xavier,Roddy, Thomas P.,Rondeau, Jean-Michel,Stauffer, Frédéric,Stout, Steven J.,Widmer, Armin,Zimmermann, Johann,Zoller, Thomas,Jahnke, Wolfgang
, p. 1884 - 1891 (2015/11/10)
Farnesyl pyrophosphate synthase (FPPS) is an established target for the treatment of bone diseases, but also shows promise as an anticancer and anti-infective drug target. Currently available anti-FPPS drugs are active-site-directed bisphosphonate inhibitors, the peculiar pharmacological profile of which is inadequate for therapeutic indications beyond bone diseases. The recent discovery of an allosteric binding site has paved the way toward the development of novel non-bisphosphonate FPPS inhibitors with broader therapeutic potential, notably as immunomodulators in oncology. Herein we report the discovery, by an integrated lead finding approach, of two new chemical classes of allosteric FPPS inhibitors that belong to the salicylic acid and quinoline chemotypes. We present their synthesis, biochemical and cellular activities, structure-activity relationships, and provide X-ray structures of several representative FPPS complexes. These novel allosteric FPPS inhibitors are devoid of any affinity for bone mineral and could serve as leads to evaluate their potential in none-bone diseases. Beyond the bone: Farnesyl pyrophosphate synthase (FPPS) is an important target for osteoporosis and bone metastases, and holds promise for a number of non-bone diseases, including cancer, parasitic infections, progeria, and Alzheimer's disease. Herein we describe two novel chemotypes of allosteric FPPS inhibitors. These are useful leads to evaluate the therapeutic potential of FPPS inhibitors for these new indications.
A General Strategy for Targeting Drugs to Bone
Jahnke, Wolfgang,Bold, Guido,Marzinzik, Andreas L.,Ofner, Silvio,Pell, Xavier,Cotesta, Simona,Bourgier, Emmanuelle,Lehmann, Sylvie,Henry, Chrystelle,Hemmig, Ren,Stauffer, Frdric,Hartwieg, J. Constanze D.,Green, Jonathan R.,Rondeau, Jean-Michel
, p. 14575 - 14579 (2016/01/25)
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.
QUINOLINES AS INHIBITORS OF FARNESYL PYROPHOSPHATE SYNTHASE
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, (2009/10/21)
The invention relates to a compound of formula (I) wherein the substituents are as described in the specification, which are useful as farnesyl pyrophosphate synthase modulators, e.g. in the treatment of proliferative diseases, to methods of manufacturing such compounds and to intermediates thereof.
