RESUMO
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.
Assuntos
Inibidores do Fator Xa , Fator Xa/química , Glicina/análogos & derivados , Glicina/química , Inibidores de Serina Proteinase/química , Cristalografia por Raios X , Humanos , Estrutura Molecular , Conformação ProteicaRESUMO
The preparation of a novel spirocyclic template from tert-butoxycarbonyl-4-piperidone is reported. The synthesis of N-(tert-butoxycarbonyl)-1-oxa-9-aza-spiro[5.5]undec-3-ene (4) for exploratory library generation involves ketone allylation, etherification, and ring-closing metathesis (RCM) reactions. Epoxidation of the alkene formed in the RCM followed by addition of volatile amines to the epoxides led rapidly to an exploratory library of structurally novel spirocyclic amino alcohols. The addition of amines to epoxides derived from 4 was determined to occur primarily at C3.
