Pharmacokinetics/pharmacodynamics of CI-1000, a purine nucleoside phosphorylase (PNP) inhibitor, in rats and monkeys.

  title={Pharmacokinetics/pharmacodynamics of CI-1000, a purine nucleoside phosphorylase (PNP) inhibitor, in rats and monkeys.},
  author={H. Hallak and A. Hayes and M. Dong and R. Gilbertsen and R. Guttendorf},
  journal={Advances in experimental medicine and biology},
Purine nucleoside Phosphorylase (PNP) is a purine salvage enzyme that catalyzes the reversible phosphorylation of guanine and hypoxanthine-based nucleosides to their respective purine bases. Patients with homozygous deficiency in PNP have markedly impaired T cell function with normal to elevated B cell function. Because of the sparing of B cell function in PNP deficiency, inhibitors of PNP are purported to have the potential to be T cell selective immunosuppressive agents with application to a… Expand
4 Citations
Purine nucleoside phosphorylases: properties, functions, and clinical aspects.
Detailed accounts are presented of design of potent inhibitors, largely nucleosides and acyclonucleosides, their phosphates and phosphonates, particularly of the human erythrocyte enzyme intended for induction of the immunodeficient state for clinical applications, such as prevention of host-versus-graft response in organ transplantations. Expand
Changes in monkey plasma purines induced by repeated doses of CI-1000, a novel inhibitor of purine nucleoside phosphorylase.
In vitro changes in CI-1000 are consistent with inhibition of PNP and the drug is approximately 10-fold more potent than a structurally related compound. Expand
Intravenous and oral pharmacokinetic study of BCX-1777, a novel purine nucleoside phosphorylase transition-state inhibitor. In vivo effects on blood 2'-deoxyguanosine in primates.
The data indicate that oral and IV administration of BCX-1777 induce a rapid rise in 2'-deoxyguanosine and that oral dosing at 8.8 and 17.6 mg/kg are at least equivalent to 4.4mg/kg IV in effecting the accumulation of 2'- deoxyguosine. Expand
The transition to magic bullets - transition state analogue drug design.
A brief history of transition state analogue design, the fundamentals behind the development of this process, and the success of enzyme inhibitors produced using this drug design methodology are looked at. Expand


Effects of 8‐Aminoguanosine, an Inhibitor of Purine Nucleoside Phosphorylase, on Plasma Nucleosides in Wistar Rats
Immunodeficient patients lacking the purine degradative enzyme purine nucleoside phosphorylase (PNP, EC have elevated PNP substrates (primarily inosine and guanosine) both in plasma andExpand
The biochemistry and pharmacology of PD 116124 (8-amino-2'-nordeoxyguanosine), an inhibitor of purine nucleoside phosphorylase (PNP).
PD 116124 produced marked and statistically significant elevation of both inosine and guanosine and was only weakly inhibitory in human mixed lymphocyte cultures, but in the presence of 10 microM dGuo, the IC50 for PD 116124 was reduced to 108.7 microM. Expand
Comparative in vitro and in vivo activities of two 9-deazaguanine analog inhibitors of purine nucleoside phosphorylase, CI-972 and PD 141955.
An in-parallel comparison is presented of the in vitro and in vivo properties of two 9-deazaguanine analog inhibitors of purine nucleoside phosphorylase (PNP) and PD 141955, with PD considerably more potent and active in all systems studied. Expand