RESUMO
Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure-activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 ≥237 µg/mL and SIF=11 µg/mL) was significantly improved over compound 1 (pH 2=5 µg/mL and SIF=0.5 µg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL=0.7 L/kg/h) compared to compound 1 (CL=3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats.
Assuntos
Azepinas/síntese química , Azepinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Azepinas/química , Azepinas/farmacocinética , Relação Dose-Resposta a Droga , Humanos , Concentração de Íons de Hidrogênio , Hiperalgesia/tratamento farmacológico , Hiperalgesia/prevenção & controle , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
A series of benzimidazole compounds containing pendant alcohol and amine moieties was found to be active against checkpoint kinase Chk2. These compounds were prepared to examine a potential hydrogen bond interaction with an active site residue and to investigate replacement of a biaryl linker with an aliphatic system in an effort to improve solubility.