1,3-Disubstituted-imidazo[1,5-a]pyrazines as insulin-like growth-factor-I receptor (IGF-IR) inhibitors

Mulvihill, Mark J.; Ji, Qunsheng; Werner, Doug; Beck, Patricia; Cesario, Cara; Cooke, Andrew; Cox, Matthew; Crew, Andrew P.; Dong, Hanqing; Feng, Lixin; Foreman, K.W.; Mak, Gilda; Nigro, Anthony; O’Connor, Matthew; Saroglou, Lydia; Stolz, Kathryn M.; Sujka, Izabela; Volk, Brian; Weng, Qinghua; Wilkes, Robin D.

doi:10.1016/j.bmcl.2006.11.016

Cited by 30 publications

(21 citation statements)

References 43 publications

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“…The imidazo[1,5- a ]pyrazine scaffold makes almost the exact same hydrophobic and hydrogen-bonding contacts as the pyrazolopyrimidine scaffold, and projects its R 1 and R 2 substituents into similar regions of the ATP-binding pockets of kinases. A number of potent and selective inhibitors of IGF1R based on the imidazopyrazine core have previously been reported [33, 34]. As expected, similar combinations of R 1 and R 2 substituents generally confer similar inhibitory activity against Pf CDPK4, independent of the scaffold.…”

Section: Resultsmentioning

confidence: 57%

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Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes

Vidadala

Ojo

Johnson

et al. 2014

European Journal of Medicinal Chemistry

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Malaria remains a major health concern for a large percentage of the world’s population. While great strides have been made in reducing mortality due to malaria, new strategies and therapies are still needed. Therapies that are capable of blocking the transmission of Plasmodium parasites are particularly attractive, but only primaquine accomplishes this, and toxicity issues hamper its widespread use. In this study, we describe a series of pyrazolopyrimidine- and imidazopyrazine-based compounds that are potent inhibitors of PfCDPK4, which is a calcium-activated Plasmodium protein kinase that is essential for exflagellation of male gametocytes. Thus, PfCDPK4 is essential for the sexual development of Plasmodium parasites and their ability to infect mosquitos. We demonstrate that two structural features in the ATP-binding site of PfCDPK4 can be exploited in order to obtain potent and selective inhibitors of this enzyme. Furthermore, we demonstrate that pyrazolopyrimidine-based inhibitors that are potent inhibitors of the in vitro activity of PfCDPK4 are also able to block P. falciparum exflagellation with no observable toxicity to human cells. This medicinal chemistry effort serves as a valuable starting point in the development of safe, transmission-blocking agents for the control of malaria.

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Section: Resultsmentioning

confidence: 57%

“…Imidazo[1,5- a ]pyrazine-based inhibitors (Table 3) were prepared using the procedure shown in Scheme 4 [33, 34]. R 2 substituents were introduced by acylating 3-(chloropyrazin-2-yl)methanamine with appropriate carboxylic acids, followed by cyclization with POCl 3 .…”

Section: Resultsmentioning

confidence: 99%

Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes

Vidadala

Ojo

Johnson

et al. 2014

European Journal of Medicinal Chemistry

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“…A series of 54 potent 1, 3 disubstituted-imidazole [1, 5-α] pyrazine derivatives with their inhibitory activities to IGF-IR were taken from the literature [12]. Only those compounds were considered whose exact pIC50 values were known.…”

Section: Methodsmentioning

confidence: 99%

“…Mulvihill et al [12] presented a binding mode of compound-2 by using FlexX based docking. Here we have also performed molecular docking of same compound.…”

Section: The Molecular Dockingmentioning

confidence: 99%

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The Receptor Guided 3D-QSAR Method is a Powerful Tool to Design More Potent IGF-1R Inhibitors

Muddassar

Pasha

Chung

et al. 2007

2007 Frontiers in the Convergence of Bioscience and Information Technologies

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Insulin-like growth factor-1 receptor (IGF-1R) has proven as a key oncology target. Recently derivatives of 1,3-disubstituted-imidazo[1,5-α] pyrazine have been found as potent IGF-IR inhibitors. Three dimensional quantitative structure activity relationship (3D-QSAR) studies have been performed for this series of compounds and validity of 3D-QSAR models compared for two major alignment schemes, namely ligand-based and receptor-guided alignment schemes. As a result, receptor guided alignment schemes yielded better 3D-QSAR models for both comparative molecular field analysis (CoMFA) (q 2 =0.53, r 2 =0.95) and comparative molecular similarity indices analysis (CoMSIA) (q 2 =0.51, r 2 =0.86). This might arise from the more accurate inhibitor alignment using structural information of the active site. Therefore the receptor-guided 3D-QSAR may be helpful to design more potent IGF-1R inhibitors as well as to understand the inhibitor binding.

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Design, synthesis, and biological evaluation of novel 3‐(thiophen‐2‐ylthio)pyridine derivatives as potential multitarget anticancer agents

Zhang

et al. 2019

Archiv der Pharmazie

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A series of novel 3‐(thiophen‐2‐ylthio)pyridine derivatives as insulin‐like growth factor 1 receptor (IGF‐1R) inhibitors was designed and synthesized. IGF‐1R kinase inhibitory activities and cytotoxicities against HepG2 and WSU‐DLCL2 cell lines were tested. For all of these compounds, potent cancer cell proliferation inhibitory activities were observed, but not through the inhibition of IGR‐1R. Selected compounds were further screened against various kinases. Typical compound 22 (50% inhibitory concentration [IC50] values, HepG2: 2.98 ± 1.11 μM and WSU‐DLCL2: 4.34 ± 0.84 μM) exhibited good inhibitory activities against fibroblast growth factor receptor‐2 (FGFR2), FGFR3, epidermal growth factor receptor, Janus kinase, and RON (receptor originated from Nantes), with IC50 values ranging from 2.14 to 12.20 μM. Additionally, the cell‐cycle analysis showed that compound 22 could arrest HepG2 cells in the G1/G0 phase. Taken together, all the experiments confirmed that the compounds in this series were multitarget anticancer agents worth further optimizing.

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1,3-Disubstituted-imidazo[1,5-a]pyrazines as insulin-like growth-factor-I receptor (IGF-IR) inhibitors

Cited by 30 publications

References 43 publications

Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes

Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes

The Receptor Guided 3D-QSAR Method is a Powerful Tool to Design More Potent IGF-1R Inhibitors

Design, synthesis, and biological evaluation of novel 3‐(thiophen‐2‐ylthio)pyridine derivatives as potential multitarget anticancer agents

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