Seijiro Akamatsu

Biological activity of chemically synthesized core sugar linked lipid a analog, heptose-(α1 → 5)-2-keto-3-deoxyoctonic acid-(α2 → 6)-2,3-diacyloxyacylglucosamine-4- phosphate

The mitogenicity, lethal toxicity and antitumor activity against Meth A fibrosarcoma and the induction of tumor necrosis factor (TNF) of chemically synthesized compounds designated as A-103, 2,3-diacyloxyacylglucosamine-4-phosphate (GlcN-4-P), and A-503), heptose-(alpha 1----5)-2-keto-3-deoxyoctonic acid (KDO)-linked GlcN-4-P (A-103), were determined. Compound A-103 induced significant incorporation of [3H]thymidine of C57BL/6 mice at 25-100 micrograms/ml, and A-503 showed the highest incorporation of [3H]thymidine at 100 micrograms/ml. The mitogenicity of A-503 exhibited a lower activity than of A-103. Compound A-503 showed no lethality at high doses of 25 and 50 micrograms/mouse in C57BL/6 mice loaded with D-galactosamine, whereas A-103 caused the death of one of three mice at a dose of 50 micrograms/mouse. Although, the two compounds with or without muramyl dipeptide showed weak antitumor activity against Meth A fibrosarcoma in BALB/c mice, but there were no remarkable differences between the compounds on antitumor activity. Peritoneal macrophages, stimulated with A-103 or A-503 caused no production of TNF which induces L929 cell lysis in vitro. These findings indicate that the addition of heptose and KDO to GlcN-4-P seems not to affect mitogenic activity, lethal toxicity, antitumor activity and TNF-production of the GlcN-4-P compound (A-103).

Pharmacological properties of YM-57029, a novel platelet glycoprotein IIb/IIIa antagonist

The pharmacological properties of YM-57029 [4-[4-(4-carbamimidoylphenyl)-3-oxopiperazin-1-yl]piperidino]acetic acid monohydrochloride trihydrate), a novel glycoprotein IIb/IIIa antagonist were examined in this study. YM-57029 inhibited fibrinogen binding to purified glycoprotein IIb/IIIa, 1000-fold more potently than the tetrapeptide arginine-glycine-aspartic acid-serine (RGDS). YM-57029 concentration-dependently inhibited ADP-, collagen- and high shear stress-induced platelet aggregation, strongly inhibited ATP release from platelets activated by ADP, and enhanced deaggregation of ADP-induced platelet aggregates. In a pro-aggregatory activity study, RGDS or SC-54701A ((S)-3-[3-[(4-amidinophenyl)carbamoyl]propionamido]-4-pentynoic acid monohydrochloride) caused prominent small aggregate formation. At a higher concentration, RGDS induced medium and large size aggregates, and SC-54701A induced medium aggregates. In contrast, YM-57029 produced only a few small and no larger size aggregates. Ex vivo ADP-induced platelet aggregation and platelet retention to collagen-coated plastic beads were dose-dependently inhibited by YM-57029 after intravenous bolus injection in guinea pigs. YM-57029 produced dose-dependent antithrombotic effects in carotid artery thrombosis and arterio-venous shunt thrombosis models in guinea pigs at 10 and 30 microg/kg, respectively. At these doses, YM-57029 prolonged template bleeding time. These results suggest that YM-57029 is a potent glycoprotein IIb/IIIa antagonist which has less pro-aggregatory effect. It may be a promising antiplatelet agent for thromboembolic diseases, and a good prototype for developing an orally active compound.