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104. 2-Chloro-4-(trifluoromethyl)pyrimidine-5-N-(3‘,5‘-bis(trifluoromethyl)phenyl)- carboxamide:  A Potent Inhibitor of NF-κB- and AP-1-Mediated Gene Expression Identified Using Solution-Phase Combinatorial Chemistry

Author

Sullivan, R. W., Bigam, C. G., Erdman, P. E., Palanki, M. S. S., Anderson, D. W., Goldman, M. E., Ransone, L. J., and Suto, M. J.

Abstract

Described is the identification of a novel series of compounds that blocks the activation of two key transcription factors, AP-1 and NF-κB. These transcription factors regulate the expression of several critical proinflammatory proteins and cytokines and represent attractive targets for drug discovery. Through the use of high throughput screening and solution-phase parallel synthesis, inhibitors of both NF-κB and AP-1 were identified. In subsequent testing, these compounds were also shown to block both IL-2 and IL-8 levels in the same cells. One of the most potent compounds in this series, 28, was active in several animal models of inflammation and immunosuppression, thus validating the importance of AP-1 and NF-κB as potential therapeutic targets. The synthesis and preliminary structure−activity relationships of these compounds is addressed.

Published
1998

105. The biochemistry and pharmacology of PD 116124 (8-amino-2'-nordeoxyguanosine), an inhibitor of purine nucleoside phosphorylase (PNP).

Author

Dong, M K, Scott, M E, Schrier, D J, Suto, M J, Sircar, J C, Black, A, Chang, T, and Gilbertsen, R B

Abstract

PD 116124 (8-amino-2'-nordeoxyguanosine; 2,8-diamino-1,9-dihydro-9- ([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)-6H-purin-6-one) is a competitive, reversible inhibitor of human purine nucleoside phosphorylase with an apparent inhibition constant of 0.41 microM. In a cell line system using human MOLT-4 and CEM T lymphoblasts and human MGL-8 and NC-37 B lymphoblasts, PD 116124 failed to inhibit [3H]thymidine uptake at concentrations up to 500 microM. However, in the presence of 10 microM 2'-deoxyguanosine (dGuo), a noninhibitory dGuo concentration by itself, PD 116124 produced potent inhibition of growth of both T cell lines but not of either B cell line. Significant elevation of intracellular 2'-deoxyguanosine triphosphate was observed in both inhibited T cell lines but not in either B cell line. Greater and more sustained accumulation of 2'-deoxyguanosine triphosphate was observed in T lymphoblasts cultured with PD 116124 plus dGuo than with dGuo only. PD 116124 was only weakly inhibitory in human mixed lymphocyte cultures (IC50 approximately equal to 1420 microM), but in the presence of 10 microM dGuo, the IC50 for PD 116124 was reduced to 108.7 microM. Administration of PD 116124 p.o. to normal male Wistar rats caused dose-dependent elevation of plasma inosine up through 500 mg/kg. Maximal inosine elevation occurred at 30 min after dosing, and elevation was significant even 24 hr after dosing. Guanosine was also elevated, although not in a dose-dependent manner. Administration of PD 116124 i.v. produced marked and statistically significant elevation of both inosine and guanosine.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1992

124. ChemInform Abstract: Inhibitors of Human Purine Nucleoside Phosphorylase. Synthesis, Purine Nucleoside Phosphorylase Inhibition, and T‐Cell Cytotoxicity of 2,5‐Diaminothiazolo(5,4‐d)pyrimidin‐7(6H)‐one and 2,5‐Diaminothiazolo(4,5‐d)pyrimidin‐7(6H)‐one. Two Thio Isosteres of 8‐Aminoguanine.

Author

SIRCAR, J. C., primary, SUTO, M. J., additional, SCOTT, M. E., additional, DONG, M. K., additional, and GILBERTSEN, R. B., additional

Published
1987
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