Vol. 301, Issue 2, 738-746, May 2002

Anti-Inflammatory Effects of a Cyclosporine Receptor-Binding Compound, D-43787

Andreas Pahl, Meixia Zhang, Katalin Török, Hildegard Kuss, Ute Friedrich, Zoltan Magyar, Jozsef Szekely, Katalin Horvath, Kay Brune and Istvan Szelenyi

Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Erlangen, Germany (A.P., M.Z., U.F., K.B.); Institute for Drug Research, Ivax Corporation, Budapest, Hungary (K.T., Z.M., J.S., K.H.); and Corporate Research and Development, ASTA Medica AG, Radebeul, Germany (H.K., I.S.)

By virtue of its binding to cyclophilin, the cellular receptor for cyclosporine (CsA), we could identify a new compound D-43787 [N-[(1-tert-butyloxycarbonyl)-indolin-2-(S)-carbonyl]-indolin-2-(S)-carbonacid-[N--benzyloxycarbonyl)-2-(S)-lysin methylester]-amide] exhibiting immunomodulating properties. It inhibited cell proliferation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin and anti-CD3/CD28 with an IC₅₀ of 0.3 µM. The protein phosphatase calcineurin, which is the target of the CsA-cyclophilin complex, is not inhibited by D-43787. It inhibited T helper cell (Th) 2 cytokines interleukin (IL)-4, -5, and -13 more effectively than the Th1 cytokine interferon (IFN)- in human primary T cells. The IC₅₀ for IL-5 and IL-13 in TPA/ionomycin-stimulated peripheral blood mononuclear cells (PBMC) is 0.7 ± 0.1 and 0.5 ± 0.1 µM, respectively, whereas the IC₅₀ for IFN- is 2.0 ± 0.4 µM. When PBMC were stimulated with anti-CD3/CD28, the IC₅₀ for IL-4, -5, and -13 were 1.5 ± 0.2, 1.8 ± 0.2, and 1.9 ± 0.4 µM, respectively. IFN- was only partially inhibited under these conditions. This effect was even more pronounced in pure CD4⁺ T cells. Pretreatment of human monocytes with D-43787 inhibited lipopolysaccharide-induced proinflammatory cytokines IL-6 and TNF with an IC₅₀ of 1.2 ± 0.1 and 4.7 ± 0.9 µM, respectively. In vivo, D-43787 potently inhibited late-phase eosinophilia in actively sensitized and challenged guinea pigs (10 mg/kg, i.p.: 51%) and Brown-Norway rats (1 mg/kg, intrapulmonary: 66% 30 mg/kg, i.p.: 50%). In adjuvant-induced arthritis, D-43787 (10-40 mg/kg, b.i.d., i.p.) dose dependently reduced edema development on both hind paws. The potency of D-43787 was comparable with that of indomethacin and dexamethasone. In conclusion, we characterized a novel Th2 selective immunosuppressive drug with possible anti-asthmatic/anti-inflammatory effects. Its mode of action is distinct from that of CsA.