RESUMO
An efficient four-step synthesis of 1-aryl-carbamoyl-2-alkyl-4-aryl-semicarbazides starting from benzophenone hydrazone is described leading to moderately active neutral factor Xa inhibitors.
Assuntos
Alcanos/síntese química , Alcanos/farmacologia , Carbamatos/síntese química , Carbamatos/farmacologia , Inibidores do Fator Xa , Semicarbazidas/síntese química , Semicarbazidas/farmacologia , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Neutral weak halothiophene benzimidazole inhibitors of the serine protease factor Xa were identified via screening of a compound library. The X-ray crystal structure of representative 3a bound to human fXa confirmed the S1 binding mode. Starting from 3a a series of halothiophene benzimidazoles was synthesized and investigated for their factor Xa inhibitory activity. This led to potent and selective achiral inhibitors against fXa such as compounds 9k and 9w.
Assuntos
Antitrombinas/síntese química , Benzimidazóis/síntese química , Inibidores do Fator Xa , Inibidores de Serina Proteinase/síntese química , Antitrombinas/farmacologia , Benzimidazóis/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Fator Xa/química , Humanos , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Tripsina/químicaRESUMO
Neutral chlorothiophenecarboxamides bearing an amino acid and a substituted aniline were synthesized and investigated for their factor Xa inhibitory activity in vitro. From selected 2-methylphenyl morpholinones the solution properties were determined. The most soluble and active compounds were then investigated in different animal species to compare the pharmacokinetic parameters. This led to a potent, water soluble and orally bioavailable candidate for further development: EMD 495235.