Novel antiallergic agents. Part I: Synthesis and pharmacology of pyrimidine amide derivatives

Ban, Masaaki; Taguchi, Hiroaki; Katsushima, Takeo; Aoki, Shoichi; Watanabe, Akihiko

doi:10.1016/s0968-0896(98)00064-9

Cited by 28 publications

(13 citation statements)

References 9 publications

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“…Pyrimidines and other nitrogen heterocycles are common pharmacophores92 and are of high biological interest 93. Pyrimidine derivatives are used as antiallergic,94 antitumor,95 antipyretic, anti‐inflammatory,96 and antiparasitic agents 97. Obrecht and co‐workers have reported a versatile cyclocondensation reaction of acetylenic ketones with a polymer‐bound isothiourea 98.…”

Section: Discussionmentioning

confidence: 99%

Solid-Phase Synthesis of Guanidinium Derivatives from Thiourea and Isothiourea Functionalities

Manimala

Anslyn

2002

Eur. J. Org. Chem.

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Guanidinium‐based compounds are biologically, medicinally, and pharmaceutically vital molecules. Due to their ability to form H‐bond interactions, charge pairing, and cation‐π interactions, guanidinium groups also perform key roles in supramolecular chemistry. They are found in nature in numerous forms and can be synthesized using different methods. Solid‐phase synthesis permits the preparation of synthetically challenging molecules and can be used for the synthesis of combinatorial libraries of lead molecules. A brief survey of methods for the synthesis of guanidiniums from thiourea and isothiourea using different reagents is discussed. (© Wiley‐VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

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Section: Discussionmentioning

confidence: 99%

Solid-Phase Synthesis of Guanidinium Derivatives from Thiourea and Isothiourea Functionalities

Manimala

Anslyn

2002

Eur. J. Org. Chem.

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“…The pyrrolo- [2,3] pyrimidines are effective inhibitors of the protein-tyrosine kinase JAK3 (56). Moreover, it was demonstrated that pyridothienopyrimidines and pyrimidine amides are effective antiallergic compounds (57,58). Several synthesized pyrimidine derivatives exhibit potent antiviral and bacteriostatic properties (59,60).…”

Section: Discussionmentioning

confidence: 99%

The Novel Calcineurin Inhibitor CN585 Has Potent Immunosuppressive Properties in Stimulated Human T Cells

Erdmann

Weiwad

Kilka

et al. 2010

Journal of Biological Chemistry

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The Ca 2؉ /calmodulin-dependent protein phosphatase calcineurin is a key mediator in antigen-specific T cell activation. Thus, inhibitors of calcineurin, such as cyclosporin A or FK506, can block T cell activation and are used as immunosuppressive drugs to prevent graft-versus-host reactions and autoimmune diseases. In this study we describe the identification of 2,6-diaryl-substituted pyrimidine derivatives as a new class of calcineurin inhibitors, obtained by screening of a substance library. By rational design of the parent compound we have attained the derivative 6-(3,4-dichloro-phenyl)-4-(N,N-dimethylaminoethylthio)-2-phenyl-pyrimidine (CN585) that noncompetitively and reversibly inhibits calcineurin activity with a K i value of 3.8 M. This derivative specifically inhibits calcineurin without affecting other Ser/Thr protein phosphatases or peptidyl prolyl cis/trans isomerases. CN585 shows potent immunosuppressive effects by inhibiting NFAT nuclear translocation and transactivation, cytokine production, and T cell proliferation. Moreover, the calcineurin inhibitor exhibits no cytotoxicity in the effective concentration range. Therefore, calcineurin inhibition by CN585 may represent a novel promising strategy for immune intervention.The activation and the precise interplay between signaling pathways are crucial for the successful initiation and progression of the immune response as a reaction of an antigen contact. In T cells the stimulation of the T cell receptor by a specific antigen leads to a calcium release from the intracellular stores and to a calcium release-activated Ca 2ϩ channel-mediated calcium influx into the cytoplasm which activates calmodulin and thereby the Ser/Thr-protein phosphatase calcineurin (1). Consequently, calcineurin represents a bottleneck in T cell receptor signaling and allows the modulation of T cell activation by low molecular compounds, such as cyclosporin A (CsA) 2 or tacrolimus (FK506) (2). The cyclic undecapeptide CsA and the macrolid FK506 bind to and inhibit the phosphatase activity of calcineurin only after interaction with their respective peptidyl prolyl cis/trans isomerases (PPIases), cyclophilins (Cyp), and FK506-binding proteins (FKBP) through a gain-of-function mechanism (3, 4). Based on their particular characteristic to bind the immunosuppressive drugs CsA and FK506, members of the Cyp and FKBP family of PPIases were also termed immunophilins (5). Among the many known PPIases, the most abundant isoforms, Cyp18 and FKBP12, were identified as major intracellular acceptor proteins for CsA and FK506, respectively. The PPIase activity of both enzymes is strongly inhibited by the immunosuppressive drugs (6), leading to many of serious side effects (e.g. nephrotoxicity, neurotoxicity, hypertension, fibrosis) that were observed in the prevention and therapy of graftversus-host reactions or autoimmune diseases (7-10). Therefore, CsA derivatives, such as [DAT-Sar] 3 CsA, were synthesized to obtain cyclophilin-independent calcineurin inhibitors (11). However, [DAT-Sar] ...

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“…In particular, pyrimidine and its derivatives occupy a key place in medicinal chemistry due to their diverse biological activities and their presence in several biologically active natural products. Synthetic pyrimidine-based scaffolds have shown to be endowed with a wide spectrum of chemotherapeutic activities such as anti-inflammatory [ 20 ], antiparasitic [ 21 ], anti-allergic [ 22 ], and antitumor activities [ 23 ]. In addition, pyrimidines are potential inhibitors of dihydrofolate reductase (DHFR), a promising drug target for the development of anti-infective agents [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Pyrimidine-oxazolidin-2-arylimino Hybrid Molecules as Antibacterial Agents

et al. 2018

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Pyrimidine-1,3-oxazolidin-2-arylimino hybrids have been synthesized as a new class of antibacterial agents. The synthetic approach exploits a Cu(II)-catalyzed intramolecular halkoxyhalogenation of alkynyl ureas, followed by a Suzuki coupling reaction with 2,4-dimethoxypyrimidin-5-boronic acid. Biological screenings revealed that most of the compounds showed moderate to good activity against two Gram-positive (B. subtilis, S. aureus) and three Gram-negative (P. aeruginosa, S. typhi, K. pneumonia) pathogenic strains. A molecular docking study, performed in the crystal structure of 50S ribosomal unit of Haloarcula marismortui, indicated that pyrimidine-oxazolidin-2-arylimino hybrids 8c and 8h exhibited a high binding affinity (−9.65 and −10.74 kcal/mol), which was in agreement with their good antibacterial activity. The obtained results suggest that the combination of pyrimidine and oxazolidone moieties can be considered as a valid basis to develop new further modifications towards more efficacious antibacterial compounds.

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Novel antiallergic agents. Part I: Synthesis and pharmacology of pyrimidine amide derivatives

Cited by 28 publications

References 9 publications

Solid-Phase Synthesis of Guanidinium Derivatives from Thiourea and Isothiourea Functionalities

Solid-Phase Synthesis of Guanidinium Derivatives from Thiourea and Isothiourea Functionalities

The Novel Calcineurin Inhibitor CN585 Has Potent Immunosuppressive Properties in Stimulated Human T Cells

Synthesis and Biological Evaluation of Pyrimidine-oxazolidin-2-arylimino Hybrid Molecules as Antibacterial Agents

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