RESUMO
Aniline 'headgroups' were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline.
Assuntos
Compostos de Anilina/síntese química , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Compostos de Anilina/administração & dosagem , Compostos de Anilina/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Receptores ErbB/metabolismo , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/síntese química , Inibidores do Crescimento/farmacologia , Humanos , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Receptor ErbB-2/metabolismoRESUMO
A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
Assuntos
Antineoplásicos/química , Receptores ErbB/antagonistas & inibidores , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Animais , Camundongos , Farmacocinética , Pirimidinas/síntese química , Pirrolidinas/síntese química , Relação Estrutura-AtividadeRESUMO
A novel series of P1 modified HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and protease inhibitor-resistant viruses. Optimization of the P1 moiety resulted in compounds with femtomolar enzyme activities and cellular antiviral activities in the low nanomolar range culminating in the identification of clinical candidate GW0385.
Assuntos
Inibidores da Protease de HIV/farmacologia , Sulfonamidas/farmacologia , Inibidores da Protease de HIV/química , Estrutura Molecular , Sulfonamidas/químicaRESUMO
A series of novel N-alkoxy-arylsulfonamide HIV protease inhibitors with low picomolar enzyme activity and single digit nanomolar antiviral activity is disclosed.
Assuntos
Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Sulfonamidas/síntese química , Derivados de Benzeno/química , Desenho de Fármacos , Farmacorresistência Viral Múltipla , Protease de HIV/efeitos dos fármacos , Humanos , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
A series of dianilinopyrimidineureas demonstrate potency as VEGFR2 kinase inhibitors.