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Séminaire Chimie ED459

The discovery of odanicatib, a cathepsin K inhibitor for the treatment of osteoporosis

Prof. Robert N. Young (Merck Frosst / Pharmaceutical Genomics and Drug Discovery, Chemistry Department, Simon Fraser University, Vancouver, Canada)

publié le , mis à jour le

Le Jeudi 03 Novembre 2011 à 13h45
UM2, salle de cours SC-16.01

Cathepsin-K (Cat-K) is an enzyme that cleaves bone matrix collagen that is released by osteoclasts as part of the bone resorption process. It was therefore proposed that an inhibitor of Cat-K would be an effective agent that would inhibit resorption and not affect the bone building action of osteoblast cells. A program was initiated in 1995 with Merck Frosst in collaboration with Axxis Pharmaceuticals (later Celera) and objectives were to find potent and very selective inhibitors as there is a large class of similar cathepsin enzymes and it was expected that inhibition of these other enzymes would lead to toxicity. Over a number of years many selective inhibitors were identified and optimized. Early inhibitors were basic molecules and were found to lose selectivity in cells as compared with in vitro enzyme assays. This was found to be due to a tendency of these molecules to concentrate in liposomes (liposomatropism). Some of the best compounds were found to have unacceptable side effects. Renewed efforts identified less basic inhibitors and from this optimization was identified odanicatib, a very potent inhibitor with excellent pharmacokinetics suitable for once a week dosing. Odanicatib has shown excellent efficacy in human clinical trials and is currently in phase 3 stage of development.

Contact local IBMM : Dr. Jean-François Hernandez


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