In vivo and in vitro pharmacologic activity of the purine nucleoside phosphorylase inhibitor BCX-34: the role of GTP and dGTP.
BCX-34 inhibits RBC PNP in vitro from humans, rats, and mice with IC50S ranging from 5 to 36 nM. BCX-34 also, in the presence but not in the absence of deoxyguanosine, inhibits human CCRF-CEM T-cell proliferation with an IC50 of 0.57 microM but not rat or mouse T-cell proliferation up to 30 microM. Inhibition of human T-cell proliferation is accompanied by an accumulation of intracellular dGTP with an associated reduction in GTP. These nucleotide changes do not occur in BC16A mouse T-cells and explain why proliferation is not inhibited by PNP inhibitors in this case. Reduction in intracellular GTP is not essential for the antiproliferative action of BCX-34. Oral bioavailability of BCX-34 in rats is 76%. BCX-34 is orally active in elevating plasma inosine in rats (2-fold at 30 mg/kg), in suppressing ex vivo RBC PNP activity in rats (98% at 3 h. 100 mg/kg), and in suppressing ex vivo skin PNP in mice (39% at 3 h, 100 mg/kg). The results demonstrate that BCX-34 inhibits human PNP and T-cell proliferation, is orally bioavailable in rodents, and pharmacologically active in vivo in rodents after oral dosing with no apparent side effects or toxicity. BCX-34 may, therefore, be useful in treating human T-cell proliferative inflammatory disorders.
BioCryst Pharmaceuticals, Inc., Birmingham, AL 35244, USA.
S
S
Bantia
J A
JA
Montgomery
H G
HG
Johnson
G M
GM
Walsh
D000818:Animals; D002478:Cells, Cultured; D003848:Deoxyguanine Nucleotides / Q000502:physiology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D016399:Lymphoma, T-Cell; D051379:Mice; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects; D014407:Tumor Cells, Cultured
D003848:Deoxyguanine Nucleotides; D007166:Immunosuppressive Agents; D006147:Guanine; C104194:peldesine; D006160:Guanosine Triphosphate; C029603:deoxyguanosine triphosphate; D011683:Purine-Nucleoside Phosphorylase