Aromatic quinolinecarboxamides as selective, orally active antibody production inhibitors for prevention of acute xenograft rejection

The prevention of xenograft rejection is substantially dependent on inhibit ing antibodies (Ab) produced by B-cells independently of T-cell signals (TI -1). Due to their ubiquitous biochemical mechanisms of action, the immunosu ppressants currently employed not only fail to discriminate between B- and T-cells but also have a narrow therapeutic window and, thus, their prolonge d use in complex immunosuppressive regimens is problematic. By capitalizing on the target enzyme-bound (DHODH) structure Ib of one of these compounds, leflunomide, and modulating part of its multiple mechanisms of action to g ain selectivity, the quinoline-8-carboxamide 3 was designed as a potentiall y weak enzyme inhibitor but effective immunosuppressant. Compound 3 fulfill ed the mechanistic criteria set and had 10-fold B-cell over T-cell selectiv ity. 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 las 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 ef fectively blocked TI-1 Ab production and suppressed Ab-mediated xenograft r ejection 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 demonstrat ing the feasibility of the development of drugs specific for impeding Ah pr oduction.