布累迪宁, 咪唑立宾, Bredinin,Mizoribine

Inhibitor of heat shock protein Hsp60; immunosuppressant.

Potent and selective inosine monophosphate dehydrogenase inhibitor (IC50 = 4 nM) Blocks T and B lymphocyte proliferation. Attenuates MCP-1 expression. Shows immunosuppressant effects in vivo.

Mizoribine is an imidazole nucleoside with immunosuppressive properties. It inhibits T cell proliferation in response to various mitogenic stimuli by 10-100% when used at concentrations ranging from 1 to 50 µg/mL. Mizoribine inhibits proliferation of stimulated T cells (IC50 = 5 µg/ml), which can be reversed by guanosine. It also inhibits guanine nucleotide formation in T cells, reducing GTP pools by 40-60% when used at a concentration of 5 µg/ml. Mizoribine inhibits replication of hepatitis C virus (HCV) RNA in vitro (IC50 = 100 µM). It suppresses glomerulosclerosis, urinary albumin excretion, interstitial fibrotic lesions, and macrophage infiltration into glomeruli and the interstitium in a rat model of type 2 diabetes when used at doses of 5 or 10 mg/kg. Mizoribine also reduces MCP-1, osteopontin (OPN), and TGF-β1 mRNA expression in the kidney in the same model. Formulations containing mizoribine have been used for the prevention of rejection after renal transplantation as well as in the treatment of lupus nephritis, rheumatoid arthritis, and primary nephritic syndrome.

Mizoribine,Mizoribine (INN, trade name Bredinin) is an immunosuppressive drug. The compound was first observed in Tokyo, Japan, in 1971. It is a natural product, first isolated from the mould Eupenicillium brefeldianum. Mizoribine (MZB) is an imidazole nucleoside that has been used in renal transplantation, and in steroid-resistant nephrotic syndrome, IgA nephropathy, lupus, as well as for adults with rheumatoid arthritis, lupus nephritis and other rheumatic diseases.

Title: Mizoribine

CAS Registry Number: 50924-49-7

CAS Name: 5-Hydroxy-1-b-D-ribofuranosyl-1H-imidazole-4-carboxamide

Additional Names: 4-carbamoyl-1-b-D-ribofuranosylimidazolium-5-olate

Manufacturers' Codes: HE-69

Trademarks: Bredinin (Toyo Jozo)

Molecular Formula: C9H13N3O6

Molecular Weight: 259.22

Percent Composition: C 41.70%, H 5.05%, N 16.21%, O 37.03%

Literature References: Nucleoside antibiotic produced by Eupenicillium brefedianum with cytotoxic and immunosuppressive activity. Isoln: K. Mizuno et al., BE 799805; eidem, US 3888843 (1973, 1975 to Toyo Jozo); eidem, J. Antibiot. 27, 775 (1974). Synthesis: M. Hayashi et al., Chem. Pharm. Bull. 23, 245 (1975); K. Fukukuwa et al., ibid. 32, 1644 (1984). Prepn of the aglycone: T. Atsumi et al., JP Kokai 76 88965 (1976 to Sumitomo), C.A. 86, 106582g (1977). HPLC determn in human serum: K. Takada et al., J. Chromatogr. 222, 156 (1981). Anti-arthritic activity: H. Iwata et al., Experientia 33, 502 (1977). Cytotoxic effect and comparison with aglycone: K. Sakaguchi et al., J. Antibiot. 28, 798 (1975). Antitumor spectrum of aglycone: N. Yoshida et al., Cancer Res. 43, 5851 (1983). Pharmacokinetics: K. Takada, Eur. J. Pharmacol. 24, 457 (1983). Clinical trials in renal transplantation: T. Inou et al., Transplant. Proc. 12, 526 (1980); eidem, ibid. 13, 315 (1981); A. Tajima et al., Transplantation 38, 116 (1984).

Properties: Crystals from methanol, mp >200° (dec). [a]D27 -35° (c = 0.8 in H2O). pKa 6.75. uv max (H2O): 245, 279 nm (E 250, 580). Sol in water. Slightly sol in methanol, ethanol. Insol in most organic solvents. LD50 in mice (g/kg): >1.5 i.v., >2.4 i.p. (Mizuno, 1975).

Melting point: mp >200° (dec)

pKa: pKa 6.75

Optical Rotation: [a]D27 -35° (c = 0.8 in H2O)

Absorption maximum: uv max (H2O): 245, 279 nm (E 250, 580)

Toxicity data: LD50 in mice (g/kg): >1.5 i.v., >2.4 i.p. (Mizuno, 1975)

Derivative Type: Aglycone

Additional Names: 5-Hydroxy-1H-imidazole-4-carboxamide; 4-carbamoyl-5-hydroxyimidazole; 4-carbamoylimidazolium-5-olate

Manufacturers' Codes: SM-108

Molecular Formula: C4H5N3O2

Molecular Weight: 127.10

Percent Composition: C 37.80%, H 3.97%, N 33.06%, O 25.18%

Therap-Cat: Immunosuppressant.

Keywords: Immunosuppressant.