Novel Inhibitor of p38 MAP Kinase as an Anti-TNF-α Drug:  Discovery of <i>N</i>-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a Potent and Orally Active Anti-Rheumatoid Arthritis Agent

Miwatashi, Seiji; Arikawa, Yasuyoshi; Kotani, Eiichi; Miyamoto, Maki; Naruo, Ken‐ichi; Kimura, Hiroyuki; Tanaka, Toshimasa; Asahi, Satoru; Ohkawa, Shigenori

doi:10.1021/jm050165o

Cited by 146 publications

(86 citation statements)

References 21 publications

(71 reference statements)

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“…30,31) The SAR of these compounds was summarized as 1) pyridyl moiety at 5-position of thiazole is important for affinity of hA 3 AR and rA 3 AR; 2) the substituent on the phenyl ring at 4-position of thiazole is related to adenosine receptor subtype selectivity; 3) the acyl moiety at 2-position of thiazole is important for affinity of rA 3 AR, as shown in Fig. 4.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

Miwatashi

Arikawa

Matsumoto

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Adenosine, an endogenous purine nucleoside, modulates a variety of physiological functions in various organs and tissues, and interacts with four specific G-protein-coupled receptor subtypes (GPCRs), classified as A 1 , A 2A , A 2B , and A 3 .1,2) All four receptors are coupled via G proteins to the adenylate cyclase-cAMP signal transduction pathway. Activation of A 1 and A 3 receptors inhibits adenylate cyclase through G i coupling, while activation of A 2A and A 2B receptors stimulates adenylate cyclase through G s coupling.3) In particular, the adenosine A 3 receptor (A 3 AR) is distributed in different organs (lung, liver, kidney, heart and brain), 4) and the potential therapeutic applications of antagonizing this receptor are proposed to be useful for the treatment of inflammation, 5) myocardial and brain ischemia, [6][7][8] and cancer. 27,28) have been reported as new hA 3 AR antagonists. Although these antagonists showed strong hA 3 AR antagonistic activity and good selectivity against other adenosine receptor subtypes, they were found to be weak or ineffective against rat A 3 AR (rA 3 AR), 1,11,12,15,28,29) and could therefore not be evaluated in rat in vivo models. The homology of A 3 AR among several species was reported and the only 72% homology between human and rat A 3 AR was one reason for species differences.28) As selective hA 3 AR antagonists that showed moderate affinity to rA 3 AR, only MRS 1191 14) and MRS 1523 15) (K i ϭ1.42, 0.113 mM, respectively) have been reported, but these activities seemed to be insufficient for evaluation in rat models. Thus, A 3 AR antagonists which show equipotent affinity and selectivity in different species have been desired for pharmacological probes on animal models, and the evaluation and selection of new drugs in preclinical phase candidates is likely to be easier.Our focus on an anti-asthmatic research program prompted us to evaluate the potential of A 3 AR antagonist as a therapeutic target. From high throughput screening, 4-phenyl-5-pyridyl-1,3-thiazole derivative 7a was identified as the preferable lead compound. We have already reported 1,3-thiazole derivatives as p38 MAP kinase inhibitors. 30,31) These compounds were bound at the ATP binding site of the kinase, and ATP is an adenosine-related compound. We therefore focused our attention on compound 7a and investigated further. In the in vitro binding assay, compound 7a showed strong hA 3 AR antagonistic activity (K i ϭ0.16 nM) and good hA 3 AR selectivity, as shown in Fig. 1. Moreover, the rA 3 AR antagonistic activity of this compound was moderate (K i ϭ23 nM). To evaluate the efficacy of the rat asthma model, improvement of the rA 3 AR antagonistic activity of 7a was critical. In the present paper, we report the discovery of a series of 2-acylamino-4-phenyl-5-pyridyl-1,3-thiazole derivatives as novel and potent antagonists against human and rat A 3 AR through structural modification based on screening hit 7a. ChemistryThe general approach for the several 4,5-disubstituted 2-acylamino-1,3-thiazoles 7 ...

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Section: Resultsmentioning

confidence: 99%

“…We have already reported 1,3-thiazole derivatives as p38 MAP kinase inhibitors. 30,31) These compounds were bound at the ATP binding site of the kinase, and ATP is an adenosine-related compound. We therefore focused our attention on compound 7a and investigated further.…”

mentioning

confidence: 99%

Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

Miwatashi

Arikawa

Matsumoto

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…For example, a recent report identified an inhibitor of p38 MAP kinase as a potent anti-TNFα drug [112].…”

Section: Future Potential Tnf Antagonistsmentioning

confidence: 99%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

260

162

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Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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“…Moreover we suggested a role for p38 in the inhibition of erythroid differentiation by TNFα, in correlation with a reversal of important erythroid transcription factors [78]. Miwatashi and colleagues already used a novel p38 presenting anemic complications [11,80].…”

Section: Deregulation Of Erythropoiesis By Tnfα α α α In Inflammationmentioning

confidence: 84%

Linking anemia to inflammation and cancer: The crucial role of TNFα

Buck

Morceau

Grigorakaki

et al. 2009

Biochemical Pharmacology

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Erythropoiesis is considered as a multistep and tightly regulated process under the control of a series of cytokines including erythropoietin (Epo). Epo activates specific signaling pathways and leads to activation of key transcription factors such as GATA-1, in order to ensure erythroid differentiation. Deregulation leads to a decreased number of red blood cells, a hemoglobin deficiency, thus a limited oxygen-carrying capacity in the blood. Anemia represents a frequent complication in various diseases such as cancer or inflammatory diseases. It reduces both quality of life and prognosis in patients. Tumor necrosis factor alpha (TNFα) was described to be involved in the pathogenesis of inflammation and cancer related anemia. Blood transfusions and erythroid stimulating agents (ESAs) including human recombinant Epo (rhuEpo) are currently used as efficient treatments. Moreover, the recently described conflicting effects of ESAs in distinct studies require further investigations on the molecular mechanisms involved in TNFα-caused anemia. The present study aims to evaluate the current knowledge and the importance of the effect of the proinflammatory cytokine TNFα on erythropoiesis in inflammatory and malignant conditions.

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Novel Inhibitor of p38 MAP Kinase as an Anti-TNF-α Drug: Discovery of N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a Potent and Orally Active Anti-Rheumatoid Arthritis Agent

Cited by 146 publications

References 21 publications

Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

TNFα blockade in human diseases: Mechanisms and future directions

Linking anemia to inflammation and cancer: The crucial role of TNFα

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