Many prosthetic surgeries result in local inflammation and bone degradation, which eventually lead to implant failure. Bisphosphonate drugs (e.g. alendronic acid) prevent bone loss in osteoporosis patients by chelating to calcium in the bone surface and by other mechanisms. The recent finding by the co-authors Cronstein et al. (Sci. Transl. Med. 2012, 4, 135ra65) suggests that selective A2A adenosine receptor (AR) agonists decrease osteolysis and promote osteoblast differentiation. In an in vivo (murine) ultrahigh-molecular weight-polypropylene wear particle-induced bone degeneration model, administration of A2AAR agonist CGS21680 reduced bone loss and associated inflammation. We envisaged combining the effects of both bisphosphonate and A2AAR agonist by linking the small molecules via PEG conjugation. Co-administration of compound 1b (hA2AAR, radioligand binding Ki = 69.2 nM) with wear particles resulted in bone regeneration with a considerable reduction in bone loss and associated inflammation. Synthetic routes to prepare the novel conjugates, in vitro binding studies and in vivo findings will be presented

In vivo effect of PEG-tethered A2A adenosine receptor agonist-alendronic acid conjugates on induced bone degeneration

2019 Spring National Meeting

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