title: Aromatic quinolinecarboxamides as selective, orally active antibody production inhibitors for prevention of acute xenograft rejection.
abstract: 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.
authors.affiliation: Transplantation Research, NOVARTIS Pharma AG, WSJ-350.314, CH-4002 Basel, Switzerland. christos.papageorgiou@pharma.novartis.com
authors.forename: C
authors.initials: C
authors.lastname: Papageorgiou
authors.forename: A
authors.initials: A
authors.lastname: von Matt
authors.forename: J
authors.initials: J
authors.lastname: Joergensen
authors.forename: E
authors.initials: E
authors.lastname: Andersen
authors.forename: K
authors.initials: K
authors.lastname: Wagner
authors.forename: C
authors.initials: C
authors.lastname: Beerli
authors.forename: T
authors.initials: T
authors.lastname: Than
authors.forename: X
authors.initials: X
authors.lastname: Borer
authors.forename: A
authors.initials: A
authors.lastname: Florineth
authors.forename: G
authors.initials: G
authors.lastname: Rihs
authors.forename: M H
authors.initials: MH
authors.lastname: Schreier
authors.forename: G
authors.initials: G
authors.lastname: Weckbecker
authors.forename: C
authors.initials: C
authors.lastname: Heusser
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D006224:Cricetinae; D015195:Drug Design; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology; D007166:Immunosuppressive Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008647:Mesocricetus; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D011804:Quinolines