Identification of 5H-chromeno[3,4-c]pyridine and 6H-isochromeno[3,4-c]pyridine derivatives as potent and selective dual ROCK inhibitors

Hu, Zilun; Wang, Cailan; Sitkoff, Doree; Cheadle, Nathan L.; Xu, Songmei; Muckelbauer, J.K.; Adam, Leonard P.; Wexler, Ruth R.; Quan, Mimi L.

doi:10.1016/j.bmcl.2020.127474

Cited by 10 publications

(8 citation statements)

References 12 publications

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“…The crystal structure of compound 27 revealed that it had the same conformation as compound 23 and showed the same hydrogen bonds (PDB ID 7JNT) (Figure 7E). 126 Among 4-phenylpyridine-based inhibitors, those exhibiting reduced conformational changes and extended side chains showed increased potency as ROCK inhibitors, providing a good strategy for ROCK inhibitor development.…”

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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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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“…It suggests that compounds 1a–d could be used to effectively treat FLT3‐ITD + cancers including ITD‐ FLT3 + acute myeloid leukemia (AML). Interestingly, compound 2 , obtained by cyclization of the pyridine and benzene ring of compound 7 , showed potent dual ROCK I and ROCK II inhibitory activity with IC 50 values of 0.67 and 0.18 nM, respectively 41 …”

Section: Synthetic Rock Inhibitorsmentioning

confidence: 99%

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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“…Several pan-ROCK inhibitors have been granted approval for human use [148][149][150][151] In particular, netarsudil has been approved by FDA for the treatment of glaucoma [151]. However, due to a lack of overall kinome selectivity of the reported dual ROCK1/2 inhibitors, there is still scope for improvement in pan-ROCK inhibitors [152]. Hu et al has recently reported the synthesis and in-vitro evaluation of a novel series of 5H-chromeno [3,4-c]pyridine, 6H-isochromeno [3,4-c] pyridine, and 6H-isochromeno [4,3-d]pyrimidine derivatives as dual ROCK1/2 inhibitors [152].…”

Section: Rho/rock Signalingmentioning

confidence: 99%

“…However, due to a lack of overall kinome selectivity of the reported dual ROCK1/2 inhibitors, there is still scope for improvement in pan-ROCK inhibitors [152]. Hu et al has recently reported the synthesis and in-vitro evaluation of a novel series of 5H-chromeno [3,4-c]pyridine, 6H-isochromeno [3,4-c] pyridine, and 6H-isochromeno [4,3-d]pyrimidine derivatives as dual ROCK1/2 inhibitors [152]. Their data show that some of the novel pan-ROCK inhibitors display potent inhibitory activity against ROCK1/2 and possess excellent kinome selectivity [152].…”

Section: Rho/rock Signalingmentioning

confidence: 99%

“…Hu et al has recently reported the synthesis and in-vitro evaluation of a novel series of 5H-chromeno [3,4-c]pyridine, 6H-isochromeno [3,4-c] pyridine, and 6H-isochromeno [4,3-d]pyrimidine derivatives as dual ROCK1/2 inhibitors [152]. Their data show that some of the novel pan-ROCK inhibitors display potent inhibitory activity against ROCK1/2 and possess excellent kinome selectivity [152]. They also provided a crystal structure of ROCK2 in complex with one of the novel dual ROCK1/2 inhibitors (PDB ID: 7JNT).…”

Section: Rho/rock Signalingmentioning

confidence: 99%

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Graft-Versus-Host Disease: Pathogenesis and Treatment

Mukai¹

2022

Purinergic System

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Graft-versus-host disease (GVHD) is a disabling complication after allogeneic hematopoietic stem cell transplantation (HSCT) and negatively impacts patients’ quality of life. GVHD is classified into 2 forms according to clinical manifestations. Acute GVHD (aGVHD) typically affects the skin, gastrointestinal tract, and liver, whereas chronic GVHD occurs systemically and shows diverse manifestations similar to autoimmune diseases such as eosinophilic fasciitis, scleroderma-like skin disease. GVHD is induced by complicated pathological crosstalk between immune cells of the host and donor and involves various signaling pathways such as purinergic signaling. Although the past several decades have seen significant progress in the understanding of mechanisms of GVHD and several drugs have been approved by FDA for the prevention and treatment of GVHD, there is still vast scope for improvement in the therapy for GVHD. Thus, new drugs for GVHD will need to be developed. Towards this goal, this chapter succinctly summarises the pathogenic process of GVHD and emerging GVHD treatments in order to provide some insights into the mechanisms of GVHD and facilitate the development of novel drugs.

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Identification of 5H-chromeno[3,4-c]pyridine and 6H-isochromeno[3,4-c]pyridine derivatives as potent and selective dual ROCK inhibitors

Cited by 10 publications

References 12 publications

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

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)

Graft-Versus-Host Disease: Pathogenesis and Treatment

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