arginyl-glycyl-aspartyl-phenylalanine and arginyl-glycyl-aspartic-acid

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.

Topics: Administration, Oral; Alkaline Phosphatase; Animals; Blood Coagulation; Calcium; Endometrial Hyperplasia; Estradiol; Female; Femur; Mice; Mice, Inbred ICR; Minerals; Models, Molecular; Molecular Conformation; Oligopeptides; Organ Size; Osteoporosis; Phosphorus; Quantitative Structure-Activity Relationship; Reference Standards; Thromboembolism; Uterus

To improve the specificity and potency of estrogen replacement therapy therapeutics while also minimizing the side effects such as bone resorption and thickening of the uterine wall, a series of novel estrogen-derived conjugates estradiol-3-RGD, estradiol-17-RGD, and estrone-3-RGD peptides have been prepared. In a mouse model, intraperitoneal (i.p.) administration of these estrogen-RGD peptide conjugates resulted in decreased serum concentrations of calcium and alkaline phosphatase, as well as increased levels of calcium, phosphorus, and minerals in the mouse femur. Furthermore, the anti-osteoporosis action of these conjugates followed a dose-dependent manner and was accompanied with no observable effects on endometrial cell hyperplasia. In addition to all of these compounds exhibiting biological activity when administered by the i.p. route, we were particularly pleased to note that the estradiol-3-RGD and estradiol-17-RGD conjugates were both orally active.

Topics: Alkaline Phosphatase; Animals; Calcium; Endometrium; Estrogen Replacement Therapy; Estrogens; Female; Hyperplasia; Mice; Oligopeptides; Organ Size; Osteoporosis; Ovariectomy

A new approach to construct a single dual-acting agent is described. Compounds 6a-c are potent free radical scavengers as demonstrated by the EC(50) values in PC12 cell survival assay in term of NO, H(2)O(2), and ()OH scavenging activity. The Ach-induced vaso-relaxation assay further confirms the potent NO scavenging activity of compounds 6a-c. In addition, 6a-c are efficacious in a rat arterial thrombosis, and are active in ADP- or PAF-induced in vitro platelet aggregation assay, suggesting that compounds 6a-c also possess anti-thrombotic activities. Since both free radical and thrombogenesis are important risk factors in myocardial ischemic/reperfusion injuries, these dual-acting agents having both free radical scavenging and antithrombolic activities may potentially be beneficial toward their treatment.

Topics: Adenosine Diphosphate; Animals; Carbolines; Drug Design; Fibrinolytic Agents; Free Radical Scavengers; Hydrogen; Molecular Structure; Oligopeptides; PC12 Cells; Phenol; Platelet Activating Factor; Platelet Aggregation; Rabbits; Rats; Thrombosis

1-(1',3'-dioxyl-4',4',5',5'-tetramethyldihydroimidazol-2'-yl)-phenyl-4-yloxylacetic acid (3), and 1-(1',3'-dioxyl-4',4',5',5'-tetramethyldihydroimidazol-2'-yl)-phenyl-4-yloxylacetyl-RGDS (13), -RGDV (14), -RGDF (15) were synthesized. The ESR measurement gave the same spectroscopy for 3 and 13-15. The NO scavenging tests in vitro, anti-platelet aggregation tests in vitro and the anti-thrombosis assay in vivo indicated that introducing 3 into the N-terminal of RGDS, RGDV and RGDF the corresponding bioactivities for both of 3 and RGD peptides can be remained completely. The present combinations provided a beneficial strategy for simultaneous scavenging NO and anti-thrombosis, and for the use of spin label of RGD peptides in the conformational researches.

Topics: Amino Acid Sequence; Nitrogen Oxides; Oligopeptides; Structure-Activity Relationship

The evolutionary process from the Arg-Gly-Asp-Phe (RGDF) tetrapeptide to potent orally active anti-platelet agents is presented. The RGD sequence is an important component in the recognition of fibrinogen by its platelet receptor GP IIb-IIIa (integrin alpha IIb beta 3). This work concentrates on the replacement of the Arg-Gly dipeptidyl fragment by an acylated aminobenzamidine. The C-terminal fragment has been replaced by a variety of beta-amino acids, expanding on a previously reported paradigm. The lead compounds showed good potency in an in vitro platelet aggregation assay (dog PRP/ADP). The affinity for the fibrinogen receptor was confirmed in several cases by the ability to inhibit 125I fibrinogen binding to activated human platelets. The ethyl ester prodrug form was tested by oral administration to dogs and monitoring of the anti-platelet effect on ex vivo collagen induced platelet aggregation. From the structural studies reported, the 4-[[(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid (5) was the best surrogate for the Arg-Gly dipeptide. Several conformationally restricted analogues are also reported which are compatible with the hypothesis of RGD binding to the alpha IIb beta 3 in a turn-extended-turn conformation. The structure-activity relationships described also underline the importance of the beta-amino acid substitution for potency. In particular, the absolute configuration at the beta-carbon was crucial for high affinity. The best acid/ester pairs reported in this study had high potency (acid PRP/ADP IC50 approximately 50 nM) and showed good oral activity in dogs at 5 mg/kg per os (ethyl ester).

Topics: Administration, Oral; Amino Acid Sequence; Animals; Benzamidines; Dogs; Female; Male; Molecular Sequence Data; Oligopeptides; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Structure-Activity Relationship