Design, synthesis and biological evaluation of 4-aryl-5-aminoalkyl-thiazole-2-amines derivatives as ROCK II inhibitors

Ma, Shuchao; Wang, Linan; Ouyang, Ben; Fan, Meixia; Qi, Jianpeng; Yao, Lei

doi:10.1016/j.bmc.2020.115683

Cited by 6 publications

(8 citation statements)

References 24 publications

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“…The docking result was similar to previous reports. (Fang et al, 2010;Ma et al, 2020;Yin et al, 2010) However, in compound 10p, the nitrogen atom of pyridine formed one H-bonding interaction with Lys216, not the residue amino acid Met172 as in compound 14c. The predicted binding mode was different to that reported by Pireddu et al (Pireddu et al, 2012) This suggested that compound 10p might adopt a different conformation in the active pocket.…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

“…The synthesis of the 4-aryl-5-aminomethyl-thiazole-2urea (10) was accomplished by five steps from commercially available materials (Scheme 1). Firstly, compound 6 was prepared by a modified route reported by Green et al (Ma et al, 2020) 4/3-acetylpyridine was treatment with pyridinium tribromide, followed by cyclization reaction with thiourea, afforded the thiazole-2-amine 6. Then an amide formation reaction between compound 6 and isonicotinic acid under classical amide condensation condition afforded the corresponding amide 7 to protect the free amino group.…”

Section: Chemistrymentioning

confidence: 99%

“…This result was consistent with previous reports. (Ma et al, 2020) For the 5-aminoalkyl side chain, the effects of dimethylamine, morpholine, pyrrolidine, and piperidine on the activity were investigated. To our surprise, the compounds with pyrrolidine groups were more potent than those of morpholine, dimethylamine, and piperidine (inhibition rate 10f> 10g> 10k, 10p> 10l).…”

Section: The Rock Inhibitory Activity Studymentioning

confidence: 99%

“…(Bandarage et al, 2018) In our lab, we previously found that compound 4 showed potent ROCK 2 inhibitory activity with an IC 50 value of 20 nM. (Ma et al, 2020) To develop diversity chemotypes as novel ROCK2 inhibitors and improve their inhibitory potency and selectivity, based on the principle of splicing and bioisosterism isometric, a series of urea-based ROCK2 inhibitors (general formula I and II) were designed, and their ROCK inhibitory activities were checked. (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of urea‐based ROCK2 inhibitors

Wang

Fan

et al. 2021

Chem Biol Drug Des

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A series of urea-based ROCK2 inhibitors were design and synthesized. The inhibitory activity on ROCK2 was screened by enzyme-linked immunosorbent assay (ELISA). The study results showed that the urea derivatives exhibited certain ROCK2 inhibitory activity. The most potent compound 10p showed ROCK2 inhibitory activity with the IC 50 value of 0.03 μM. A preliminary structure-activity relationship was then summarized. The molecular docking studies showed that further optimization needs to conduct to obtain more potent ROCK inhibitors.

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Section: Molecular Docking Studiesmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: The Rock Inhibitory Activity Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of urea‐based ROCK2 inhibitors

Wang

Fan

et al. 2021

Chem Biol Drug Des

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“…A series of 4-aryl-5-aminoalkyl-thiazole-2-amines were designed and synthesized as ROCK inhibitors. Representative compound 25 showed a high affinity for ROCK2 (IC 50 = 20 nM) (Figure C) …”

Section: Rock Inhibitorsmentioning

confidence: 99%

Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives

et al. 2023

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Rho-associated coiled-coil-containing kinases (ROCKs), serine/threonine protein kinases, were initially identified as downstream targets of the small GTP-binding protein Rho. Pulmonary fibrosis (PF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Interestingly, ROCK activation has been demonstrated in PF patients and in animal PF models, making it a promising target for PF treatment. Many ROCK inhibitors have been discovered, and four of these have been approved for clinical use; however, no ROCK inhibitors are approved for the treatment of PF patients. In this article, we describe ROCK signaling pathways and the structure–activity relationship, potency, selectivity, binding modes, pharmacokinetics (PKs), biological functions, and recently reported inhibitors of ROCKs in the context of PF. We will also focus our attention on the challenges to be addressed when targeting ROCKs and discuss the strategy of ROCK inhibitor use in the treatment of PF.

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Recent advances in the development of Rho kinase inhibitors (2015–2021)

Yao

2023

Medicinal Research Reviews

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Rho‐associated coiled‐coil kinases (ROCKs) are key downstream effectors of small GTPases. ROCK plays a central role in diverse cellular events with accumulating evidence supporting the concept that ROCK is important in tumor development and progression. Numerous ROCK inhibitors have been investigated for their therapeutic potential in the treatment of cancers. In this article, we review recent research progress on ROCK inhibitors, especially those with potential for the treatment of cancers, reported in the literature from 2015 to 2021. Most ROCK inhibitors show potent in vitro and in vivo antitumor activities and have potential in the treatment of cancers.

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Design, synthesis and biological evaluation of 4-aryl-5-aminoalkyl-thiazole-2-amines derivatives as ROCK II inhibitors

Cited by 6 publications

References 24 publications

Design, synthesis, and biological evaluation of urea‐based ROCK2 inhibitors

Design, synthesis, and biological evaluation of urea‐based ROCK2 inhibitors

Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives

Recent advances in the development of Rho kinase inhibitors (2015–2021)

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