Comparative in vitro and in vivo activities of two 9-deazaguanine analog inhibitors of purine nucleoside phosphorylase, CI-972 and PD 141955
| Autor: | Jagadish C. Sircar, M. C. Conroy, Usha Josyula, Wu Wen-Shen, David J. Wilburn, Ml K. Dong, Richard B. Gilbertsen |
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| Rok vydání: | 1992 |
| Předmět: |
Male
Guanine T-Lymphocytes Guanosine Purine nucleoside phosphorylase Thiophenes Biology Biochemistry Cell Line chemistry.chemical_compound In vivo medicine Animals Humans Deoxyguanosine Inosine Pharmacology chemistry.chemical_classification Dose-Response Relationship Drug Deoxyguanine Nucleotides Rats Inbred Strains Molecular biology Rats Pyrimidines Enzyme Purine-Nucleoside Phosphorylase chemistry Enzyme inhibitor biology.protein medicine.drug |
| Zdroj: | Biochemical Pharmacology. 44:996-999 |
| ISSN: | 0006-2952 |
| Popis: | 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), CI-972 [8-amino-9-deaza-9-(3-thienylmethyl)guanine] and PD 141955 [9-deaza-9-(3-thienylmethyl)guanine] (published K i values of 0.83–8.0 and 0.08 μM, respectively). Despite structural similarities, PD 141955 was considerably more potent and active in all systems studied. The respective ic 50 values for inhibition of MOLT-4 cell growth in the absence and presence of 10 μM 2'-deoxyguanosine (GdR) were > 50 and 5.06 μM for CI-972 and 15.4 and 0.061 μM for PD 141955. PD 141955 induced accumulation of dGTP in GdR-treated MOLT-4 and CEM cells at log-lower concentrations than were required of CI-972, and the magnitude of dGTP accumulation in PD 141955-treated T cell cultures was markedly greater (e.g. 366 vs 100 pmol 10 6 CEM cells at 10 μM). PD 141955 administered orally produced a dose-dependent elevation of plasma inosine and guanosine in rats over a broad concentration range. Mean plasma inosine concentrations following a 150 mg kg p.o. dose peaked at 6.21 and 13.2 μM in CI-972 and PD 141955-treated rats, respectively. Low levels of inosine were detectable at 50 μg kg following oral administration of PD 141955. |
| Databáze: | OpenAIRE |
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