Anti-inflammatory effects of a cyclosporine receptor-binding compound, D-43787.

Abstract

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-epsilon-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 IC(50) of 0.3 microM. 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)-gamma in human primary T cells. The IC(50) 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 microM, respectively, whereas the IC(50) for IFN-gamma is 2.0 +/- 0.4 microM. When PBMC were stimulated with anti-CD3/CD28, the IC(50) for IL-4, -5, and -13 were 1.5 +/- 0.2, 1.8 +/- 0.2, and 1.9 +/- 0.4 microM, respectively. IFN-gamma 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 TNFalpha with an IC(50) of 1.2 +/- 0.1 and 4.7 +/- 0.9 microM, 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.

• Authors: Andreas Pahl, Meixia Zhang, Katalin Török, Hildegard Kuss, Ute Friedrich, Zoltan Magyar, Jozsef Szekely, Katalin Horvath, Kay Brune, Istvan Szelenyi
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 301 Issue 2 Pg. 738-46 (May 2002) ISSN: 0022-3565 [Print] United States
• PMID: 11961080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Immunosuppressive Agents
• Indoles
• N-(N-((1-tert-butyloxycarbonyl)indolin-2-carbonyl)indolin-2-carbonyl)-(N-epsilon-benzyloxycarbonyl)-2-lysine methyl ester
• Cyclosporine
• Cyclophilin A
• Peptidylprolyl Isomerase
• Lysine

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Arthritis, Experimental (drug therapy)
• Asthma (prevention & control)
• Cell Division (drug effects)
• Cyclophilin A (drug effects, metabolism)
• Cyclosporine (pharmacology)
• Cytokines (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Guinea Pigs
• Humans
• Immunosuppressive Agents (pharmacology, therapeutic use)
• Indoles (chemistry, pharmacology, therapeutic use)
• Injections, Intraperitoneal
• Injections, Subcutaneous
• Leukocytes, Mononuclear (cytology, drug effects)
• Lysine (analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Male
• Peptidylprolyl Isomerase (metabolism)
• Rats
• Rats, Inbred BN
• Rats, Inbred Lew
• Th1 Cells (drug effects, metabolism)
• Th2 Cells (drug effects, metabolism)