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Chemical Compound Review:

CHEMBL554876 3,8-diamino-9-(thiophen-3- ylmethyl)-2,4,7...

Synonyms: CI-972, AG-J-13955, ACMC-20cnfo, AC1L4TYI, AC1Q3EMP, ...

This record was replaced with 163977.

Gilbertsen, R.B. et al., Gilbertsen, R.B. et al., Wilburn, D.J. et al., Boehncke, W.H. et al., Sircar, J.C. et al.

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Disease relevance of 4,8-diamino-7-(3-thienylmethyl)-3,5,9-triazabicyclo[4.3.0]nona-3,7,10-trien-2-one

To elucidate the potential use of PNP inhibitors in the therapy of cutaneous T-cell lymphomas (CTCLs) the authors studied the effects of CI-1000 (formerly PD141955-2) and CI-972 on a T-cell line MyLa established from a patient with mycosis fungoides [1].

High impact information on 4,8-diamino-7-(3-thienylmethyl)-3,5,9-triazabicyclo[4.3.0]nona-3,7,10-trien-2-one

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 [2].
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 [3].
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. 2.4.2.1., Ki = 0.83 microM) entering clinical trials as a T cell-selective immunosuppressive agent [3].
PD 141955 and CI-972: 9-deazaguanine analog purine nucleoside phosphorylase inhibitors. I. Suppression of the human mixed lymphocyte reaction (MLR) [4].

Anatomical context of 4,8-diamino-7-(3-thienylmethyl)-3,5,9-triazabicyclo[4.3.0]nona-3,7,10-trien-2-one

Thus, consistent with its greater PNP inhibitory activity in a cell free system, PD 141955 is significantly more potent than CI-972 in its ability to suppress the MLR [4].

Associations of 4,8-diamino-7-(3-thienylmethyl)-3,5,9-triazabicyclo[4.3.0]nona-3,7,10-trien-2-one with other chemical compounds

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 Ki values of 0.83-8.0 and 0.08 microM, respectively) [5].

References

Evidence for a pathway independent from 2'-deoxyguanosine and reversible by IL-2 by which purine nucleoside phosphorylase inhibitors block T-cell proliferation. Boehncke, W.H., Gilbertsen, R.B., Hemmer, J., Sterry, W. Scand. J. Immunol. (1994) [Pubmed]
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, J.C., Kostlan, C.R., Gilbertsen, R.B., Bennett, M.K., Dong, M.K., Cetenko, W.J. J. Med. Chem. (1992) [Pubmed]
Selective in vitro inhibition of human MOLT-4 T lymphoblasts by the novel purine nucleoside phosphorylase inhibitor, CI-972. Gilbertsen, R.B., Dong, M.K., Kossarek, L.M., Sircar, J.C., Kostlan, C.R., Conroy, M.C. Biochem. Biophys. Res. Commun. (1991) [Pubmed]
PD 141955 and CI-972: 9-deazaguanine analog purine nucleoside phosphorylase inhibitors. I. Suppression of the human mixed lymphocyte reaction (MLR). Wilburn, D.J., Dong, M.K., Gilbertsen, R.B. Agents Actions (1993) [Pubmed]
Comparative in vitro and in vivo activities of two 9-deazaguanine analog inhibitors of purine nucleoside phosphorylase, CI-972 and PD 141955. Gilbertsen, R.B., Josyula, U., Sircar, J.C., Dong, M.K., Wu, W.S., Wilburn, D.J., Conroy, M.C. Biochem. Pharmacol. (1992) [Pubmed]

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