CI 972 - CAS 115787-68-3
Catalog number: 115787-68-3
Category: Inhibitor
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This active molecular is a potent purine nucleoside phosphorylase inhibitor and a T cell-selective immunosuppressive agent. CI-972 inhibited proliferation of human MOLT-4 (T cell) and not MGL-8 (B cell) lymphoblasts with respective IC50s of 3.0 and greater than 50 microM when tested with 10 microM 2'-deoxyguanosine. In Apr 1996, Immunological Disorders section added to drug profile and Immunological disorders in USA was discontinued.
CI 972; CI972; CI-972. 4H-Pyrrolo(3,2-d)pyrimidin-4-one, 2,6-diamino-1,5-dihydro-7-(3-thienylmethyl)-, monohydrochloride
Soluble in DMSO
-20°C Freezer
Immunological disorders; Transplant rejection
Quality Standard:
In-house standard
Shelf Life:
2 month in rt, long time
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1.Blockade of nucleoside degradation in monkey whole blood in vitro by CI-1000, a purine nucleoside phosphorylase (PNP) inhibitor.
Gilbertsen RB;Dong MK Adv Exp Med Biol. 1994;370:167-71.
Purine nucleosides HxR or GdR (2.5 micrograms/mL blood) were added to EDTA-treated cynomolgus monkey whole blood in vitro, alone or with the PNP inhibitor CI-1000 (1 microgram/mL), mixed, and the concentration of nucleosides remaining in plasma followed as a function of time. The half-lives of GdR and HxR in control blood were 1.2 and < 1 min, respectively, and were extended to 17.8 and 39.8 min, respectively, by coaddition of CI-1000. In contrast, a structural analog of CI-1000, CI-972, when tested in parallel at 1 microgram/mL, had markedly less effect on the breakdown of either nucleoside. The ability of CI-1000 to retard nucleoside breakdown in blood in vitro may be a predictor of in vivo activity, and can be viewed as an early and essential biochemical consequence of PNP inhibition culminating in immunosuppression.
2.Inhibitors of human purine nucleoside phosphorylase. Synthesis of pyrrolo[3,2-d]pyrimidines, a new class of purine nucleoside phosphorylase inhibitors as potentially T-cell selective immunosuppressive agents. Description of 2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d] pyrimidin-4-one.
Sircar JC;Kostlan CR;Gilbertsen RB;Bennett MK;Dong MK;Cetenko WJ J Med Chem. 1992 May 1;35(9):1605-9.
Purine nucleoside phosphorylase (PNP) is a purine-metabolizing enzyme in the purine cascade and has been a target for drug design for sometime. A series of potent human PNP inhibitors, pyrrolo[3,2-d]pyrimidines (9-deazaguanines), has been synthesized and evaluated in the enzyme assay and in the cell line assay using MOLT-4 (T-cell) and MGL-8 (B-cell) lymphoblasts for selectivity. One of the compounds, 2,6-diamino-3,5- dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidine-4-one (11c; CI-972), was found to be moderately potent, competitive, and reversible inhibitor of PNP with Ki = 0.83 microM. It was also found to be selectively cytotoxic to MOLT-4 lymphoblasts (IC50 = 3.0 microM) but not to MGL-8 lymphoblasts and was evaluated further. Compound 11c (CI-972) is under development in the clinic.
3.Selective in vitro inhibition of human MOLT-4 T lymphoblasts by the novel purine nucleoside phosphorylase inhibitor, CI-972.
Gilbertsen RB;Dong MK;Kossarek LM;Sircar JC;Kostlan CR;Conroy MC Biochem Biophys Res Commun. 1991 Aug 15;178(3):1351-8.
CI-972 (2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2- d]pyrimidin-4-one monohydrochloride, monohydrate) is a competitive inhibitor of PNPase (E.C., Ki = 0.83 microM) entering clinical trials as a T cell-selective immunosuppressive agent. Neither CI-972 (less than or equal to 50 microM) nor dGuo (less than or equal to 10 microM) inhibited [3H]Thd uptake by human MOLT-4 (T cell) or MGL-8 (B cell) lymphoblasts, but in the presence of 10 microM dGuo, the IC50 for CI-972 decreased to 3.0 microM for MOLT-4 but remained at greater than 50 microM for MGL-8. Inhibition of MOLT-4 growth was associated with an increase in dGTP that was dependent on CI-972 concentration and inhibited by 2'-deoxycytidine. Growth could not be restored by hypoxanthine or adenine. No alterations in GTP pools were noted in MOLT-4, and neither GTP nor dGTP were altered in MGL-8.
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