Discovery of a novel twin drug from Phillygenin and glucosamine for osteoarthritis treatment.

The search for novel anti-OA agents that combine high efficacy with long-term safety remains a great challenge. Herein, we wish to disclose the distinct combined effect of TCM-derived lipophilic phillygenin and naturally-occurred hydrophilic glucosamine (GlcN) in OA treatment, which enables the subsequent design and syntheis of a series of twin drugs from these two OA therapeutic agents via the formation of glycosidic bond and further derivatization of amine group. Among them, twin drug 6 with an unsubstituted amine group and β-configuration exhibited the nost significant and dose-dependent in vivo anti-OA activity while no apparent toxicity was observed. In particular, it displayed comparable therapeutic efficacy and more favorable safety profiles compared to the clinically-used diacerein (DIA) and functions via multiple cellular mechanisms ranging from osteoclast differentiation inhibition and anti-inflammation/anti-oxidation to cartilage protection. Overall, our findings highlight 6 as a promising candidate for anti-OA drug discovery.