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

摘要

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-oste oporosis activity was evaluated, and the results showed significantly higher oral anti-osteoporosis potency and lower risks of thrombogenesis and endometrial hyperplasia than those of estradiol and 6 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 compara tively exact anti-osteoporosis activity for a conjugate.