title: GPIIb/IIIa integrin antagonists with the new conformational restriction unit, trisubstituted beta-amino acid derivatives, and a substituted benzamidine structure.
abstract: Ethyl N-[3-(2-fluoro-4-(thiazolidin-3-yl(imino)methyl)benzoyl)amino-2, 2-dimethylpentanoyl]piperidine-4-acetate 40 (NSL-96184) is a highly potent and orally active fibrinogen receptor antagonist, which is characterized by the presence of the trisubstituted beta-amino acid residue, 3-ethyl-2,2-dimethyl-beta-alanine. This compound was developed on the basis of the SAR study of N-[3-(N-4-amidinobenzoyl)amino-2, 2-dimethyl-3-phenylpropionyl]piperidine-4-acetic acid 1(NSL-95301) with the derivatization focused on the central trisubstituted beta-amino acid unit as well as the basic amidinobenzoyl unit, and the esterification of the carboxyl group for prodrug composition. Compound 1, which was reported in our previous study, was discovered by the application of combinatorial chemistry. The molecular modeling study suggests that the trisubstituted beta-amino acid unit is responsible for fixing the molecule to its active conformation. Compound 40 showed an excellent profile in the in vitro and in vivo studies for its human platelet aggregation inhibitory activity and oral availability in guinea pigs. This oral availability largely depends on the modification of the amidino group with a cyclic secondary amine, i.e., thiazolidine in 40. In in vivo studies, the onset of the antiplatelet action of 40 is very fast after oral administration, whereas its duration of action is relatively short. These results suggest that 40 has an excellent therapeutic potential, especially for antithrombotic treatment in the acute phase. 3-Substituted-2,2-dimethyl-beta-amino acid residues would serve as new and useful linear templates to restrict the conformational flexibility of peptidomimetics.
authors.affiliation: Life Science Research Center, Advanced Technology Research Laboratories, Nippon Steel Corporation, 3-35-1 Ida, Nakahara-ku, Kawasaki 211-0035, Japan. yhayashi@Lab1.nsc.co.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.forename: J
authors.initials: J
authors.lastname: Katada
authors.forename: T
authors.initials: T
authors.lastname: Harada
authors.forename: A
authors.initials: A
authors.lastname: Tachiki
authors.forename: K
authors.initials: K
authors.lastname: Iijima
authors.forename: Y
authors.initials: Y
authors.lastname: Takiguchi
authors.forename: M
authors.initials: M
authors.lastname: Muramatsu
authors.forename: H
authors.initials: H
authors.lastname: Miyazaki
authors.forename: T
authors.initials: T
authors.lastname: Asari
authors.forename: T
authors.initials: T
authors.lastname: Okazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.forename: E
authors.initials: E
authors.lastname: Yasuda
authors.forename: M
authors.initials: M
authors.lastname: Yano
authors.forename: I
authors.initials: I
authors.lastname: Uno
authors.forename: I
authors.initials: I
authors.lastname: Ojima
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001550:Benzamidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D053778:Thiazolidines
chemical_list: D001550:Benzamidines; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D053778:Thiazolidines; C112867:ethyl N-(3-(2-fluoro-4-(thiazolidin-3-yl(imino)methyl)benzoyl)amino-2,2-dimethylpentanoyl)piperidine-4-acetate