Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure–activity relationships of pyrimidine-5-carboxamide derivatives

Hisamichi, Hiroyuki; Naito, Ryo; Toyoshima, Akira; Kawano, Noriyuki; Ichikawa, Atsushi; Orita, Akiko; Orita, Masaya; Hamada, Naoko; Takeuchi, Makoto; Ohta, Mitsuaki; Tsukamoto, Shin‐ichi

doi:10.1016/j.bmc.2005.05.033

Cited by 50 publications

(40 citation statements)

References 22 publications

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“…BAY-61-3606, identified by Yamamoto et al, is an imidazopyrimidine analogue that selectively inhibits Syk activity to treat allergic diseases [96]. Pyrimidine-5-carboxamides families, such as YM193306 and other derivatives developed by Hisamichi et al are also Syk inhibitors to treat allergic diseases [97]. …”

Section: Syk-targeted Drug Developmentmentioning

confidence: 99%

Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

Son

Ryou

et al. 2014

Mediators of Inflammation

148

175

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Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk) was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases.

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Section: Syk-targeted Drug Developmentmentioning

confidence: 99%

Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

Son

Ryou

et al. 2014

Mediators of Inflammation

148

175

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“…The effect of MNS on the osteosarcoma cell lines was compared with a src inhibitor and three additional syk inhibitors [12, 31, 32]. Although the effect of MNS was confirmed in these experiments (Figures 8(a)–8(c)), neither the src or other syk inhibitors, alone or in combination, mimicked the effects of MNS on motility (Figure 8(a)) or colony formation (Figures 8(b) and 8(c)).…”

Section: Resultsmentioning

confidence: 99%

Osteosarcoma Phenotype Is Inhibited by 3,4-Methylenedioxy-β-nitrostyrene

Messerschmitt

Rettew

Schroeder

et al. 2012

Sarcoma

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β-nitrostyrene compounds, such as 3,4-methylenedioxy-β-nitrostyrene (MNS), inhibit growth and induce apoptosis in tumor cells, but no reports have investigated their role in osteosarcoma. In this study, human osteosarcoma cell families with cell lines of varying tumorigenic and metastatic potential were utilized. Scrape motility assays, colony formation assays, and colony survival assays were performed with osteosarcoma cell lines, both in the presence and absence of MNS. Effects of MNS on human osteoblasts and airway epithelial cells were assessed in monolayer cultures. MNS decreased metastatic cell line motility by 72–76% and colony formation by 95–100%. MNS consistently disrupted preformed colonies in a time-dependent and dose-dependent manner. MNS had similar effects on human osteoblasts but little effect on airway epithelial cells. An inactive analog of MNS had no detectable effects, demonstrating specificity. MNS decreases motility and colony formation of osteosarcoma cells and disrupts preformed cell colonies, while producing little effect on pulmonary epithelial cells.

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“…One such derivative, 2-(2-aminoethylamino)-4-{3-(trifluoromethyl)phenylamino}pyrimidine-5-carboxamide, exhibited significant inhibition of the PCA reaction in mice following subcutaneous administration (Hisamichi et al, 2005). Another potent Syk kinase inhibitor, namely R112, from the 2,4-diaminopyrimidine class, inhibited degranulation induced by anti IgE crosslinking in both mast cells and basophils, uniquely inhibiting not only degranulation, but also lipid mediator and cytokine production.…”

Section: {2-[7-(34-dimethoxyphenyl)-imidazo[12-c] Pyrimidin-5-ylamimentioning

confidence: 98%