RESUMO
Novel substituted 2-anilino- and 2-cycloalkylaminoquinoxalines have been found to be useful and selective inhibitors of PDGF-R autophosphorylation. Replacement of an anilino-substituent with substituted cyclohexylamino- or norbornylamino substituents led to significant improvements in the pharmacokinetic profile of these analogues.
Assuntos
Quinoxalinas/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Angioplastia Coronária com Balão/efeitos adversos , Aorta/citologia , Divisão Celular/efeitos dos fármacos , Reestenose Coronária/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinoxalinas/farmacologia , Relação Estrutura-AtividadeRESUMO
RPR127963 demonstrates an excellent pharmacokinetic profile in several species and was found to be efficacious in the prevention of restenosis in a Yucatan mini-pig model upon oral administration of 1-5 mg/kg. The in vitro selectivity profile and SAR of the highly optimized PDGF-R tyrosine kinase inhibitor are highlighted.
Assuntos
Quinoxalinas/síntese química , Quinoxalinas/farmacocinética , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Divisão Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Colágeno/biossíntese , Sistema Enzimático do Citocromo P-450/biossíntese , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinoxalinas/farmacologia , Ratos , Relação Estrutura-Atividade , SuínosRESUMO
Activities of vascular smooth muscle cells (SMCs) such as proliferation, migration, and matrix production contribute to restenosis following clinical interventions of angioplasty and stent placement. Because activation of platelet-derived growth factor (PDGF)-receptor tyrosine kinase (PDGFr-TK) influences these processes and promotes restenosis, TKI963, an inhibitor of the PDGFr-TK was discovered, and its efficacy was evaluated in blocking stent-induced restenosis as analyzed by intravascular ultrasound (IVUS). TKI963, a low-molecular-weight compound, inhibited the cell-free PDGFbetar-TK with a K(i) value of 56 +/- 14 nM. TKI963 also inhibited PDGF-dependent events in human aortic SMCs (e.g., in situ PDGFr autophosphorylation, mitogenesis, chemotaxis, and collagen production with median inhibitory concentration values of approximately 300 nM) without affecting the activity of a series of membrane receptor tyrosine kinases and intracellular serine/threonine kinases. In vivo, stent-induced restenosis in the swine coronary artery was reduced by oral administration of TKI963 (1.25, 2.5, and 5 mg/kg BID, for 28 days). Late lumen cross-sectional area (CSA) loss, plaque CSA growth, and plaque volume in the stent determined by IVUS were dose-relatedly decreased (33-62% at 1.25 mg/kg BID to 66-92% at 5 mg/kg BID, depending on the parameter) compared with controls. TKI963 treatment of =1 week following stent placement had no effect on the prevention of restenosis. TKI963, a selective, orally bioavailable inhibitor of the PDGFr-TK, dose-relatedly reduced stent-induced restenosis and did so by inhibiting PDGF-dependent activities that occur as late events following stent placement.