RESUMO
A search for noncarbohydrate sLe(x) mimics led to the development of quinic acid derivatives as selectin inhibitors. At Wyeth we solved the first cocrystal structure of a small molecule, quinic acid, with E-selectin. In the cocomplex two hydroxyls of quinic acid mimic the calcium-bound fucose of the tetrasaccharide sLe(x). The X-ray structure, together with structure based computational methods, was used to design quinic acid based libraries that were synthesized and evaluated for their ability to block the interaction of sLex with P-selectin. A large number of analogues were prepared using solution-phase parallel synthesis. Selected compounds showed decrease in leukocyte rolling in the IVM mouse model. Compound 2 inhibited neutrophil influx in the murine TIP model and demonstrated good plasma exposure.
Assuntos
Selectina E/metabolismo , Oligossacarídeos/química , Ácido Quínico/análogos & derivados , Ácido Quínico/farmacologia , Animais , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Fucose , Veias Jugulares/efeitos dos fármacos , Veias Jugulares/fisiologia , Cinética , Antígenos do Grupo Sanguíneo de Lewis , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Oligossacarídeos/síntese química , Oligossacarídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Antígeno Sialil Lewis X , Ressonância de Plasmônio de SuperfícieRESUMO
Recombinant human interleukin (IL)-11 is a multifunctional cytokine with hematopoietic, immunomodulatory, and epithelial cell protective activities. IL-11alpha receptors are expressed on the luminal surface of intestinal epithelial cells. It was hypothesized that orally administered IL-11 would prevent mucosal damage and protect against microbial invasion in a neutropenic rat model of gram-negative sepsis. IL-11 was administered daily by enteric, coated multiparticle pellets over the course of chemotherapy-induced neutropenia. Compared with the placebo group, IL-11-treated rats retained mucosal mass and had prolonged survival time, reduced pathologic changes, and reduced systemic levels of bacterial endotoxin and concentrations of Pseudomonas aeruginosa in target tissues. Enterocyte messenger RNA levels for tumor necrosis factor-alpha and interferon-gamma revealed that oral IL-11 reduced but did not prevent increased expression of these cytokine genes. These results indicate that orally administered IL-11 may preserve epithelial cell integrity in the presence of cytoreductive chemotherapy. This may represent a new treatment strategy for the prevention of infection in neutropenic hosts.