Novel Inhibitors of the Nuclear Factor of Activated T Cells (NFAT)-Mediated Transcription of .beta.-Galactosidase: Potential Immunosuppressive and Antiinflammatory Agents

Abstract

The preparation of a series of quinazoline-2,4-diones, 1-3, and pyrrolo[3,4-d]pyrimidine-2,4-diones, 4-8 is described. A small number of quinazolinedione analogs were identified from random screening to possess low micromolar (1.3-4.4 microM) potency in the nuclear factor of activated T cells-1-regulated beta-galactosidase expression assay. An expanded analog search resulted in identifying pyrrolopyrimidinedione 4b which is 5-10-fold (0.26 microM) more potent than the quinazolinediones. Replacement of the benzyl group with naphthyl led to greater potency and conformationally restricted analogs 4u-w. The naphthyl and acenaphthyl analogs are 10-100 times more potent inhibitors of beta-galactosidase expression than 4b. Binding affinity data for displacement of radiolabeled 4s from Jurkat cell membranes reflected an excellent correlation with the IC50 value for inhibition of beta-galactosidase activity. These products, whose structure-activity relationships are discussed, are of interest as potential agents for preventing interleukin-2 gene transcription.

Preclinical Efficacy of the Novel Monocarboxylate Transporter 1 Inhibitor BAY-8002 and Associated Markers of Resistance

“…The high-affinity lactate transporter MCT1 is therefore considered to be an attractive target for cancer therapy. To date, only one class of MCT1/2-specific inhibitors has been described, which was originally identified in a phenotypic screen for immune-suppressants (13). In this study, we established a dedicated cellular high-throughput screening assay for the identification of MCT1 inhibitors, based on the fluorescent pH indicator SNARF-5.…”

“…Therefore, MCT1 inhibition has been recognized as an attractive therapeutic strategy, and one MCT1 inhibitor, AZD3965, is currently under clinical investigation. AZD3965 belongs to a class of compounds that has originally been identified in a phenotypic screen for use in immunosuppression (12)(13)(14). We have designed a dedicated cell-based screen and identified a novel class of MCT1 inhibitors, including the potent and orally available MCT1 inhibitor BAY-8002.…”

NFATc2 Modulates Microglial Activation in the AβPP/PS1 Mouse Model of Alzheimer’s Disease

“…Nevertheless, selective NFAT inhibition strategies are still required since adverse side effects of both CsA and FK-506 exist due to their indirect inhibitory mechanism that relies on inhibition of the phosphatase, calcineurin [63]. For example, small molecule [64, 65] as well as peptide based inhibitors [33, 36, 39, 41, 45, 66–70] of NFAT but not calcineurin have been described. It is likely that continued preclinical development in this area will produce agents with the immunomodulatory action of NFAT inhibition without the adverse consequences of nephrotoxicity associated with FK-506 and CsA [71, 72].…”

Bioisoterism Review- An Biological Modification

“…Another illustration of divalent bioisosteric linkers is observed in the study of inhibitors of the nuclear factor of activated T cells (NFAT)-mediated transcription of β-galactosidase [17] T Table 4. Here again the similar bond angles and electronegativities (Tables 3 and 4) of the -NH-and -CH2-bioisosteric linkers result in analogues which retain activity.…”