title: Pharmacological properties of YM-57029, a novel platelet glycoprotein IIb/IIIa antagonist.
abstract: 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.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Moritani
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sato
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shigenaga
authors.forename: Nami
authors.initials: N
authors.lastname: Hisamichi
authors.forename: Masato
authors.initials: M
authors.lastname: Ichihara
authors.forename: Seijiro
authors.initials: S
authors.lastname: Akamatsu
authors.forename: Ken ichi
authors.initials: Ki
authors.lastname: Suzuki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nii
authors.forename: Seiji
authors.initials: S
authors.lastname: Kaku
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Inagaki
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Tomioka
authors.forename: Isao
authors.initials: I
authors.lastname: Yanagisawa
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001550:Benzamidines / Q000494:pharmacology; D019921:Biotinylation; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008863:Microspheres; D009842:Oligopeptides / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D013314:Stress, Mechanical
chemical_list: C462000:(4-(4-(4-carbamimidoylphenyl)-3-oxopiperazin-1-yl)piperidino)acetic acid monohydrochloride trihydrate; D001550:Benzamidines; D005343:Fibrinolytic Agents; D009842:Oligopeptides; D010879:Piperazines; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C097215:SC 54701A; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005340:Fibrinogen; D003094:Collagen; C046617:arginyl-glycyl-aspartyl-serine