Synthesis, evaluation and 3D QSAR analysis of novel estradiol–RGD octapeptide conjugates with oral anti-osteoporosis activity

To enhance the potency, reduce the side effects and improve oral property of estradiol in estrogen replacement therapy (ERT), 6 novel estradiol–RGD octapeptide conjugates have been prepared. In an ovariectomized mouse osteoporotic model, at an oral dosage of 110.3 nmol/kg per day, their anti-osteoporosis activity was significantly higher than that of estradiol and estradiol–RGD tetrapeptide conjugates, and their risks of thrombogenesis and endometrial hyperplasia were significantly lower than that of estradiol and estradiol–RGD tetrapeptide conjugates. Using QSAR module of Cerius2, the 3D QSAR was performed for both femur weights and femur ash weights of estradiol–RGD peptide conjugates receiving mice. The r2 of the 3D QSAR equations up to 0.995 and 0.988 indicates that they are capable of predicting a comparatively exact anti-osteoporosis activity for a conjugate.

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