The discovery of novel 3-aryl-indazole derivatives as peripherally restricted pan-Trk inhibitors for the treatment of pain

Shirahashi, Hiromitsu; Toriihara, Eisuke; Suenaga, Yoshihito; Yoshida, Hideyuki; Akaogi, Kensuke; Endou, Yukiko; Wakabayashi, Makoto; Takashima, Misako

doi:10.1016/j.bmcl.2019.06.018

Cited by 11 publications

(4 citation statements)

References 17 publications

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“…15 ) of pan-Trk for the treatment of pain. 76 Among the synthesized compounds by varying the substitution in ring A, compound 39a with a methoxypyridine moiety was found to exhibit the highest potency but moderate metabolic stability. Replacement of the methoxy group with piperidine (39b) led to high cell permeability and significant potency (TRKA IC 50 = 1.6 nM).…”

Section: Mono-kinase Inhibitorsmentioning

confidence: 98%

Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer

et al. 2021

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Section: Mono-kinase Inhibitorsmentioning

confidence: 98%

Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer

et al. 2021

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“…The ratio of compound 88 in brain to plasma was found to be only 0.03 after an i.p. injection of 2.5 mg/kg in rats [ 98 ].…”

Section: Pyrazole-based Trk Inhibitorsmentioning

confidence: 99%

Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects

et al. 2022

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Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011–2020).

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“…The availability of several structures of TrkA in the protein data bank enabled the use of chemoinformatic approaches for the development of new Trk inhibitors. For example, a structure-based drug design approach led to the discovery of 3-pyrazolyl-indazole 1 ( Figure 1 ) as a potent pan-Trk inhibitor with low brain penetration ability and in vivo activity in a thermal hypersensitivity inflammatory pain model induced by Complete Freund’s Adjuvant (CFA) [ 12 ].…”

Section: Tyrosine Kinase (Tk) Groupmentioning

confidence: 99%

Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

et al. 2021

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The purpose of this review is to underline the protein kinases that have been established, either in fundamental approach or clinical trials, as potential biological targets in pain management. Protein kinases are presented according to their group in the human kinome: TK (Trk, RET, EGFR, JAK, VEGFR, SFK, BCR–Abl), CMGC (p38 MAPK, MEK, ERK, JNK, ASK1, CDK, CLK2, DYRK1A, GSK3, CK2), AGC (PKA, PKB, PKC, PKMζ, PKG, ROCK), CAMK, CK1 and atypical/other protein kinases (IKK, mTOR). Examples of small molecule inhibitors of these biological targets, demonstrating an analgesic effect, are described. Altogether, this review demonstrates the fundamental role that protein kinase inhibitors could play in the development of new pain treatments.

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The discovery of novel 3-aryl-indazole derivatives as peripherally restricted pan-Trk inhibitors for the treatment of pain

Cited by 11 publications

References 17 publications

Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer

Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer

Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects

Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

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