RESUMO
Cyclic heptapeptide 1, which contains an Arg-Gly-Asp sequence, has good affinity for the platelet receptor GPIIb-IIIa and was chosen for study by 1H NMR techniques. The key RGD sequence of this molecule was found to reside in a conformationally defined type II' Gly-Asp beta-turn, and this information was used in the design of simple non-peptide RGD mimics. Disubstituted isoquinolones, bearing an acidic side chain at position 2 and a basic side chain at position 6, were prepared and were found to have modest affinity for GPIIb-IIIa. Systematic modification of the basic residue contained in these molecules yielded compounds with high affinity for GPIIb-IIIa.
Assuntos
Oligopeptídeos/química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Ácido Aspártico , Desenho de Fármacos , Ensaio de Imunoadsorção Enzimática , Glicina , Humanos , Modelos Químicos , Modelos Moleculares , Mimetismo Molecular , Oligopeptídeos/farmacologia , Agregação Plaquetária , Estrutura Secundária de Proteína , Relação Estrutura-AtividadeRESUMO
Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, 5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage, although the latter enhances activity. Several compounds in this series provided measurable blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester generally provided compounds which gave greater systemic exposure after oral administration. Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.
Assuntos
Benzopiranos/síntese química , Isoquinolinas/síntese química , Oligopeptídeos/química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Tetra-Hidronaftalenos/síntese química , Administração Oral , Animais , Benzopiranos/química , Benzopiranos/farmacocinética , Benzopiranos/farmacologia , Ligação Competitiva , Disponibilidade Biológica , Ensaio de Imunoadsorção Enzimática , Cobaias , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Mimetismo Molecular , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Estrutura Secundária de Proteína , Ratos , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacocinética , Tetra-Hidronaftalenos/farmacologiaRESUMO
A novel series of 1,2-disubstituted indole, azaindole and benzimidazole derivatives possessing an amine moiety was identified as thrombin inhibitors. An indole with basic diamine moieties (12a) was the most potent thrombin inhibitor in the series with Kass= 197 x 10(6) L/mol.
Assuntos
Anticoagulantes/síntese química , Compostos Aza/síntese química , Benzimidazóis/síntese química , Indóis/síntese química , Trombina/antagonistas & inibidores , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Anticoagulantes/química , Anticoagulantes/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Desenho de Fármacos , Indóis/química , Indóis/farmacologia , Cinética , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.