RESUMO
A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various amide modifications and substitution on the left side phenyl ring were prepared and found to show significant inhibitory activities towards both CXCR2 and CXCR1 receptors.
Assuntos
Amidas/química , Ciclobutanos/síntese química , Diaminas/síntese química , Fenol/química , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Administração Oral , Animais , Área Sob a Curva , Química Farmacêutica/métodos , Ciclobutanos/farmacologia , Diaminas/farmacologia , Desenho de Fármacos , Humanos , Inflamação , Cinética , Modelos Químicos , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 3,4- and 3,5-disubstituted phenyl-containing cyclobutenedione analogues were synthesized and evaluated as CXCR2 receptor antagonists. Variations in the disubstitution pattern of the phenyl ring afforded new compounds with potent CXCR2 binding affinity in the low nanomolar ranges. Moreover, two potent compounds 19 and 26 exhibited good oral pharmacokinetic profiles.
Assuntos
Ciclobutanos/síntese química , Ciclobutanos/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Ciclobutanos/química , Haplorrinos , Estrutura Molecular , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.