The synthesis of a new series of 4-N-piperazinyl-thieno[2,3-d]pyrimidines is described. The synthetic route allows introducing structural variety at positions 2, 4 and 6 of the scaffold. Evaluation of their immunosuppressive activity in a Mixed Lymphocyte Reaction (MLR) assay revealed that the most potent compound has an IC(50)-value of 66 nM and therefore deserves attention for further medicinal chemistry optimization.
[Show abstract][Hide abstract] ABSTRACT: The synthetic potency of readily accessible, ethyl 2-amino-4-methyl-5-(4-nitrophenoxy)thiophene-3-carboxylate (1) as a versatile precursor for the synthesis of novel polyfunctionally substituted thienopyrimidines is reported. The latter derivatives undergo further heterocyclisation to the related polycyclic fused systems via reactions with different reagents.
Journal of Chemical Research 10/2010; 34(10). DOI:10.3184/030823410X12863009209478 · 0.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Herein we describe the synthesis and in vitro and in vivo activity of thiazolo[5,4-d]pyrimidines as a novel class of immunosuppressive agents, useful for preventing graft rejection after organ transplantation. This research resulted in the discovery of a series of compounds with potent activity in the mixed lymphocyte reaction (MLR) assay, which is well-known as the in vitro model for in vivo rejection after organ transplantation. The most potent congeners displayed IC(50) values of less than 50 nM in this MLR assay and hence are equipotent to cyclosporin A, a clinically used immunosuppressive drug. One representative of this series was further evaluated in a preclinical animal model of organ transplantation and showed excellent in vivo efficacy. It validates these compounds as new promising immunosuppressive drugs.
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