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 r(2) 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.
Liu
Jiangyuan
J
College of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China.
Zhang
Xiaoyi
X
Zhao
Ming
M
Peng
Shiqi
S
D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002118:Calcium / Q000097:blood / Q000378:metabolism; D004714:Endometrial Hyperplasia / Q000139:chemically induced; D004958:Estradiol / Q000737:chemistry*; D005260:Female; D005269:Femur / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008903:Minerals / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D010024:Osteoporosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D010758:Phosphorus / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D012015:Reference Standards; D013923:Thromboembolism / Q000139:chemically induced; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D008903:Minerals; D009842:Oligopeptides; D010758:Phosphorus; D004958:Estradiol; C047981:arginyl-glycyl-aspartic acid; D000469:Alkaline Phosphatase; D002118:Calcium