RESUMEN
The prevention of xenograft rejection is substantially dependent on inhibiting antibodies (Ab) produced by B-cells independently of T-cell signals (TI-1). Due to their ubiquitous biochemical mechanisms of action, the immunosuppressants currently employed not only fail to discriminate between B- and T-cells but also have a narrow therapeutic window and, thus, their prolonged use in complex immunosuppressive regimens is problematic. By capitalizing on the target enzyme-bound (DHODH) structure 1b of one of these compounds, leflunomide, and modulating part of its multiple mechanisms of action to gain selectivity, the quinoline-8-carboxamide 3 was designed as a potentially weak enzyme inhibitor but effective immunosuppressant. Compound 3 fulfilled the mechanistic criteria set and had 10-fold B-cell over T-cell selectivity. Its pyridyl analogue 4 was found to be a highly potent and selective B-cell immunosuppressant with a 75-fold selectivity for B- over T-cells (as judged by the MLR data) and no general cytotoxicity at concentrations up to 160-fold higher than those required to inhibit B-cells. In the mouse, 4 effectively blocked TI-1 Ab production and suppressed Ab-mediated xenograft rejection in a xenotransplantation model under a once-daily dosing regimen, with efficacy down to 0.3 mg/kg/day po. These are the first data demonstrating the feasibility of the development of drugs specific for impeding Ab production.
Asunto(s)
Linfocitos B/efectos de los fármacos , Rechazo de Injerto/prevención & control , Inmunosupresores/síntesis química , Quinolinas/síntesis química , Trasplante Heterólogo/inmunología , Animales , Formación de Anticuerpos/efectos de los fármacos , Linfocitos B/inmunología , Cricetinae , Diseño de Fármacos , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Corazón/inmunología , Inmunosupresores/sangre , Inmunosupresores/química , Inmunosupresores/farmacología , Lipopolisacáridos/farmacología , Mesocricetus , Ratones , Ratones Desnudos , Modelos Moleculares , Conformación Molecular , Quinolinas/química , Quinolinas/farmacocinética , Quinolinas/farmacología , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Based on the structural comparison of the S1 pocket in different trypsin-like serine proteases, a series of Boc-D-trimethylsilylalanine-proline-boro-X pinanediol derivatives, with boro-X being different amino boronic acids, have been synthesized as inhibitors of thrombin. Among the novel compounds, a number of derivatives were synthesized which appeared to have side-chain variants too big to fit into the S1 pocket. Nevertheless, these compounds inhibited thrombin in the nM range. The X-ray structure of one of these inhibitors bound to the active side of thrombin reveals that a new binding mode is responsible for these surprising results.