Purine nucleoside phosphorylase inhibitor BCX-1777 (Immucillin-H)--a novel potent and orally active immunosuppressive agent.

Abstract

Patients with purine nucleoside phosphorylase (PNP) deficiency present a selective T-cell immunodeficiency. Inhibitors of PNP are, therefore, of interest as potential T-cell selective immunosuppressive agents. BCX-1777 is a potent inhibitor of PNP from various species including human, mouse, rat, monkey and dog, with IC50 values ranging from 0.48 to 1.57 nM. BCX-1777, in the presence of 2'-deoxyguanosine (dGuo, 3-10 microM), inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction (MLR) and phytohemagglutinin (PHA) (IC50 values < 0.1-0.38 microM). BCX-1777 is a 10-100-fold more potent inhibitor of human lymphocyte proliferation than other known PNP inhibitors like PD141955 and BCX-34. Nucleotide analysis of human lymphocytes indicate that inhibition of proliferation by BCX-1777 correlates with dGTP levels in the cells. BCX-1777 has excellent oral bioavailability (63%) in mice. At a single dose of 10 mg/kg in mice, BCX-1777 elevates dGuo to approximately 5 microM. BCX-1777 was not effective in mouse T-cell models such as delayed type hypersensitivity (DTH) and splenomegaly because mouse T-cells do not accumulate dGTP as do human T-cells. However, in the human peripheral blood lymphocyte severe combined immunodeficiency (hu-PBL-SCID) mouse model, BCX-1777 was effective in prolonging the life span 2-fold or more. This is the first known example of a PNP inhibitor that elevates dGuo in mice similar to the levels observed in PNP-deficient patients. Furthermore, these dGuo levels are also required for in vitro T-cell inhibition by BCX-1777. Thus, BCX-1777 represents a novel class of selective immunosuppressive agents that could have therapeutic utility in various T-cell disorders.

• Authors: S Bantia, P J Miller, C D Parker, S L Ananth, L L Horn, J M Kilpatrick, P E Morris, T L Hutchison, J A Montgomery, J S Sandhu
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 1 Issue 6 Pg. 1199-210 (Jun 2001) ISSN: 1567-5769 [Print] Netherlands
• PMID: 11407314 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Immunosuppressive Agents
• Indicators and Reagents
• Purine Nucleosides
• Pyrimidinones
• Pyrroles
• forodesine
• Guanosine Triphosphate
• Purine-Nucleoside Phosphorylase

Topics

• Administration, Oral
• Animals
• Biological Availability
• Enzyme Inhibitors (pharmacokinetics, pharmacology)
• Graft vs Host Reaction (drug effects)
• Guanosine Triphosphate (metabolism)
• Immunosuppressive Agents (pharmacology)
• Indicators and Reagents
• Injections, Intravenous
• Lymphocyte Culture Test, Mixed
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Purine Nucleosides
• Purine-Nucleoside Phosphorylase (antagonists & inhibitors)
• Pyrimidinones (pharmacokinetics, pharmacology)
• Pyrroles (pharmacokinetics, pharmacology)
• Survival Analysis
• T-Lymphocytes (drug effects, immunology)