Tag: 463.5719

Discovery and optimization of novel pyrazole-benzimidazole CPL304110 as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1-3) was written by Yamani, Abdellah;Zdzalik-Bielecka, Daria;Lipner, Joanna;Stanczak, Aleksandra;Piorkowska, Natalia;Stanczak, Paulina Seweryna;Olejkowska, Patrycja;Hucz-Kalitowska, Joanna;Magdycz, Marta;Dzwonek, Karolina;Dubiel, Krzysztof;Lamparska-Przybysz, Monika;Popiel, Delfina;Pieczykolan, Jerzy;Wieczorek, Maciej. And the article was included in European Journal of Medicinal Chemistry in 2021.Synthetic Route of C26H33N5O3 This article mentions the following:

The scaffolds hybridization approach, scaffold-hopping concept, has been employed to synthesize a series of novel pyrazole-benzimidazoles I [R¹ = H, Cl; R² = morpholin-4-yl, 4-methylpiperazin-1-ylcarbonyl, tetrahydropyran-4-ylcarbamoyl, etc.; R³ = H, F]. Compound I [R¹ = R³ = H; R² = 4-methylpiperazin-1-yl] (CPL304110) was identified as a selective and potent pan-FGFR inhibitor for FGFR1, FGFR2, FGFR3 with IC₅₀ of 0.75 nM, 0.50 nM, 3.05 nM resp., and IC₅₀ of 87.90 nM for FGFR4. Due to its favorable pharmacokinetic profile, low toxicity and potent anti-tumor activity in-vivo, this compound I is currently under evaluation in phase I clin. trial for the treatment of bladder, gastric and squamous cell lung cancers (01FGFR2018; NCT04149691). In the experiment, the researchers used many compounds, for example, rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3Synthetic Route of C26H33N5O3).

rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3) belongs to piperazine derivatives. Piperazine belongs to the family of medicines called anthelmintics. Piperazine is an anthelminthic especially useful in the treatment of partial intestinal obstruction caused by Ascaris worms, which is a condition primarily seen in children. Piperazine hydrate and piperazine citrate are the main anthelminthic piperazines.Synthetic Route of C26H33N5O3

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors was written by Brameld, Ken A.;Owens, Timothy D.;Verner, Erik;Venetsanakos, Eleni;Bradshaw, J. Michael;Phan, Vernon T.;Tam, Danny;Leung, Kwan;Shu, Jin;LaStant, Jacob;Loughhead, David G.;Ton, Tony;Karr, Dane E.;Gerritsen, Mary E.;Goldstein, David M.;Funk, Jens Oliver. And the article was included in Journal of Medicinal Chemistry in 2017.Formula: C26H33N5O3 This article mentions the following:

Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clin. validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncol. indications. An irreversible covalent binding mechanism imparts many desirable pharmacol. benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chem. optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor. In the experiment, the researchers used many compounds, for example, rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3Formula: C26H33N5O3).

rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3) belongs to piperazine derivatives. Industrial applications of piperazine include the manufacture of plastics, resins, pesticides and brake fluids. Piperazines are very broad chemical group, covering a wide range of drugs from antidepressants to antihistamines. The connecting property of all these chemicals is the presence of a piperazine functional group.Formula: C26H33N5O3

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

ODM-203, a selective inhibitor of FGFR and VEGFR, shows strong antitumor activity, and induces antitumor immunity was written by Holmstrom, Tim H.;Moilanen, Anu-Maarit;Ikonen, Tarja;Bjorkman, Mari L.;Linnanen, Tero;Wohlfahrt, Gerd;Karlsson, Stefan;Oksala, Riikka;Korjamo, Timo;Samajdar, Susanta;Rajagopalan, Srinivasan;Chelur, Shekar;Narayanan, Kishore;Ramachandra, Raghuveer K.;Mani, Jiju;Nair, Rashmi;Gowda, Nagaraj;Anthony, Thomas;Dhodheri, Samiulla;Mukherjee, Subhendu;Ujjinamatada, Ravi K.;Srinivas, Nanduri;Ramachandra, Murali;Kallio, Pekka J.. And the article was included in Molecular Cancer Therapeutics in 2019.Related Products of 1035270-39-3 This article mentions the following:

Alterations in the gene encoding for the FGFR and upregulation of the VEGFR are found often in cancer, which correlate with disease progression and unfavorable survival. In addition, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-mol. FGFR kinase inhibitors are currently in clin. development. ODM-203 is a novel, selective, and equipotent inhibitor of the FGFR and VEGFR families. In this report we show that ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC50 6-35 nmol/L) in biochem. assays. In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC50 33 nmol/L) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50-150 nmol/L). In vivo, ODM-203 shows strong antitumor activity in both FGFR-dependent xenograft models and in an angiogenic xenograft model at similar well-tolerated doses. In addition, ODM-203 inhibits metastatic tumor growth in a highly angiogenesis-dependent kidney capsule syngenic model. In the experiment, the researchers used many compounds, for example, rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3Related Products of 1035270-39-3).

rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3) belongs to piperazine derivatives. Piperazine is a fairly basic compound and is an amine solvent. Piperazine and its salts did not induce point mutations in a bacterial test. A series of mutagenicity studies in cells, both in vitro and in vivo, has been completed and showed no evidence of mutagenic effect.Related Products of 1035270-39-3

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression was written by Kotani, H.;Ebi, H.;Kitai, H.;Nanjo, S.;Kita, K.;Huynh, T. G.;Ooi, A.;Faber, A. C.;Mino-Kenudson, M.;Yano, S.. And the article was included in Oncogene in 2016.SDS of cas: 1035270-39-3 This article mentions the following:

Targeted therapies are effective in subsets of lung cancers with EGFR mutations and anaplastic lymphoma kinase (ALK) translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in 10-20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarker-directed fibroblast growth factor receptor (FGFR) inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal growth factor receptor (EGFR) inhibitors and ALK inhibitors, resp. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression and protein expression of FGFR1 were assessed in cell lines, tumor specimens and data from The Cancer Genome Atlas. The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors. Further interrogation of the receptor tyrosine kinase activity in these discordant cell lines revealed co-activation of HER2 and platelet-derived growth factor receptor-α (PDGFRα) caused by gene amplification or ligand overexpression maintained phosphoinositide 3-kinase (PI3K) and MEK/ERK signaling even in the presence of FGFR inhibitor. Accordingly, co-inhibition of FGFR1 and HER2 or PDGFRα led to enhanced drug responses. In contrast, FGFR1-amplified high FGFR1 protein-expressing lung cancers are sensitive to FGFR inhibitor monotherapy by downregulating ERK signaling. Addition of a PI3K inhibitor to these high FGFR1 protein-expressing cancers further sensitized them to FGFR inhibitor. These data reveal that biomarker-directed trials for FGFR1-amplified SCC require assessment of FGFR1 protein expression and uncover novel therapeutic strategies for FGFR1-amplified SCC with low FGFR1 protein expression. In the experiment, the researchers used many compounds, for example, rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3SDS of cas: 1035270-39-3).

rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3) belongs to piperazine derivatives. A form in which piperazine is commonly available industrially is as the hexahydrate, C4H10N2. 6H2O, which melts at 44 °C and boils at 125–130 °C. Outside the body, piperazine has a remarkable power to dissolve uric acid and producing a soluble urate, but in clinical experience it has not proved equally successful. SDS of cas: 1035270-39-3

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Identification of FGFR3-TACC3 gene fusion in metastatic gastric cancer was written by Kim, Youjin;Kim, Seung Tae;Lee, Jeeyun;Kang, Won Ki;Kim, Kyoung-Mee;Park, Se Hoon. And the article was included in Precision and Future Medicine in 2018.Category: piperazines This article mentions the following:

In preclin. cancer models, fibroblast growth factor receptor (FGFR) gene aberration has been known to be associated with increased tumor cell proliferation and survival in several cancer types. Oncogenic fusions consisting of FGFR3 and transforming acid coiled coil 3 (TACC3) had been identified as potential therapeutic target. We report on a gastric cancer patient with liver metastases who harbored FGFR3-TACC3 fusion which is extremely rare in gastrointestinal cancer. Herein, we report a case presentation with literature review of FGFR3-TACC3 fusion. In the experiment, the researchers used many compounds, for example, rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3Category: piperazines).

rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3) belongs to piperazine derivatives. Piperazine belongs to the family of medicines called anthelmintics. Although many piperazine derivatives occur naturally, piperazine itself can be synthesized by reacting alcoholic ammonia with 1,2-dichloroethane, by the action of sodium and ethylene glycol on ethylene diamine hydrochloride, or by reduction of pyrazine with sodium in ethanol.Category: piperazines

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

A miRNA Panel Predicts Sensitivity of FGFR Inhibitor in Lung Cancer Cell Lines was written by Ren, Shengxiang;Rivard, Christopher J.;Yu, Hui;Genova, Carlo;Rozenboom, Leslie;Gao, Dexiang;Hinz, Trista K.;Rikke, Brad A.;Wynes, Murry W.;Caldwell, Charles;Agustoni, Francesco;Kenichi suda;Jiang, Tao;Zhou, Caicun;Heasley, Lynn E.;Hirsch, Fred R.. And the article was included in Clinical Lung Cancer in 2018.Related Products of 1035270-39-3 This article mentions the following:

To test whether a microRNA (miRNA) panel may serve as an alternative biomarker of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor sensitivity in lung cancer.Histol. diverse lung cancer cell lines were submitted to assays for ponatinib and AZD4547 sensitivity. miRNAs, FGFR1 mRNA, gene copy number, and protein expression were detected by real-time quant. PCR, fluorescence in-situ hybridization, and immunoblotting in 34 lung cancer cell lines.Among 34 cell lines, 14 exhibited ponatinib sensitivity and 20 exhibited AZD4547 sensitivity (drug concentration causing 50% inhibition values < 100 nmol/L). A total of 39 of the 377-miRNA set were initially identified from the 4 paired ponatinib-sensitive or -insensitive cell lines to have at least an 8-fold differential expression and then were detected in all the 34 cell lines. The miRNA panel performed similar to FGFR1 protein expression (AUC = 0.864) and mRNA expression (AUC = 0.939), and better than FGFR1 amplification (AUC = 0.696). Furthermore, we validated this panel using data for sensitivity to AZD4547 in the cell line cohort with an AUC of 0.931 and a sensitivity of 73.3% and specificity of 76.2%, resp.The developed miRNA panel (let-7c, miRNA155, and miRNA218) may be useful in predicting response to FGFR tyrosine kinase inhibitors, either ponatinib or AZD4547 in lung cancer cell lines, and warrants further validation in the clin. setting. In the experiment, the researchers used many compounds, for example, rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3Related Products of 1035270-39-3).

rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3) belongs to piperazine derivatives. Piperazine causes primary dermal irritation and skin burns at high concentrations. Piperazine also causes eye irritation in humans. Although many piperazine derivatives occur naturally, piperazine itself can be synthesized by reacting alcoholic ammonia with 1,2-dichloroethane, by the action of sodium and ethylene glycol on ethylene diamine hydrochloride, or by reduction of pyrazine with sodium in ethanol.Related Products of 1035270-39-3

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Inhibition of Fibroblast Growth Factor Receptor by AZD4547 Protects Against Inflammation in Septic Mice was written by Huang, Yueyue;Wang, Fen;Li, Hao;Xu, ShunYao;Xu, Wenwei;Pan, XiaoJun;Hu, Yufeng;Mao, Lingjie;Qian, Songzan;Pan, Jingye. And the article was included in Inflammation in 2019.Related Products of 1035270-39-3 This article mentions the following:

Sepsis is a life-threatening condition caused by the dysregulated host immune response to infection characterized by excessive secretion of inflammatory factors. AZD4547 is a selective inhibitor of fibroblast growth factor receptors that participates in the inflammatory response. The aim of this study was to investigate the inflammation-targeting effects and related mol. mechanisms of AZD4547 in sepsis using a cecal ligation and puncture model and RAW264.7 macrophages stimulated with lipopolysaccharide. AZD4547 improved the survival of CLP mice and exhibited a robust protective function against lung damage histol. Pretreatment with AZD4547 significantly alleviated the expression of the pro-inflammatory factors IL-1β, IL-6, TNF-α, MMP9, and CXCL10 both in vivo and in vitro. In addition, AZD4547 suppressed the proliferative activity of macrophages in lung tissue and RAW264.7 macrophages. In addition, the LPS-induced phosphorylation of key proteins of NF-κB/MAPK/STAT3 pathways in RAW264.7 macrophages, such as p65, IκB-α, Erk1/2, JNK, and STAT3 proteins, could be inhibited by AZD4547 pretreatment. In conclusion, AZD4547 exerts a protective effect against excessive inflammatory damage in septic mice and may have the potential for use as an effective drug for the management of sepsis. In the experiment, the researchers used many compounds, for example, rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3Related Products of 1035270-39-3).

rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3) belongs to piperazine derivatives. Industrial applications of piperazine include the manufacture of plastics, resins, pesticides and brake fluids. Piperazine and its salts did not induce point mutations in a bacterial test. A series of mutagenicity studies in cells, both in vitro and in vivo, has been completed and showed no evidence of mutagenic effect.Related Products of 1035270-39-3

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Discovery and optimization of novel pyrazole-benzimidazole CPL304110 as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1-3) was written by Yamani, Abdellah;Zdzalik-Bielecka, Daria;Lipner, Joanna;Stanczak, Aleksandra;Piorkowska, Natalia;Stanczak, Paulina Seweryna;Olejkowska, Patrycja;Hucz-Kalitowska, Joanna;Magdycz, Marta;Dzwonek, Karolina;Dubiel, Krzysztof;Lamparska-Przybysz, Monika;Popiel, Delfina;Pieczykolan, Jerzy;Wieczorek, Maciej. And the article was included in European Journal of Medicinal Chemistry in 2021.Synthetic Route of C26H33N5O3 This article mentions the following:

The scaffolds hybridization approach, scaffold-hopping concept, has been employed to synthesize a series of novel pyrazole-benzimidazoles I [R¹ = H, Cl; R² = morpholin-4-yl, 4-methylpiperazin-1-ylcarbonyl, tetrahydropyran-4-ylcarbamoyl, etc.; R³ = H, F]. Compound I [R¹ = R³ = H; R² = 4-methylpiperazin-1-yl] (CPL304110) was identified as a selective and potent pan-FGFR inhibitor for FGFR1, FGFR2, FGFR3 with IC₅₀ of 0.75 nM, 0.50 nM, 3.05 nM resp., and IC₅₀ of 87.90 nM for FGFR4. Due to its favorable pharmacokinetic profile, low toxicity and potent anti-tumor activity in-vivo, this compound I is currently under evaluation in phase I clin. trial for the treatment of bladder, gastric and squamous cell lung cancers (01FGFR2018; NCT04149691). In the experiment, the researchers used many compounds, for example, rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3Synthetic Route of C26H33N5O3).

rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3) belongs to piperazine derivatives. Piperazine belongs to the family of medicines called anthelmintics. Piperazine is an anthelminthic especially useful in the treatment of partial intestinal obstruction caused by Ascaris worms, which is a condition primarily seen in children. Piperazine hydrate and piperazine citrate are the main anthelminthic piperazines.Synthetic Route of C26H33N5O3

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Systematic profiling of staralog response to acquired drug resistant kinase gatekeeper mutations in targeted cancer therapy was written by Yang, Yuping;Qiu, Yue;Liu, Xu;Liu, Yanhua;Yin, Yaling;Li, Peng. And the article was included in Amino Acids in 2020.Safety of rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide This article mentions the following:

Here, we describe an integrative approach to systematically profile the mol. response of 15 representative Staralogs to 17 kinase gatekeeper mutations in targeted cancer therapy. With the profile we are able to divide gatekeeper mutations into three classes (i.e. classes I, II and III) and to divide Staralogs into two groups (i.e. groups 1 and 2) using heuristic clustering. The class I and II mutations confer consistent sensitivity and resistance for all Staralogs, resp., while the class III mutations address divergent effects on different Staralogs. The mutations to Ile residue can generally reduce Staralog affinity by inducing unfavorable steric hindrance, whereas the mutations to Met and Leu residues would improve Staralog affinity by establishing favorable S···p interaction, van der Waals packing and/or hydrophobic contact. The group 1 and 2 Staralogs are primarily determined by carbonyl or hydroxyl substitution state at the position 7 of Staralog core, where points to kinase gatekeeper residue and can thus be directly influenced by gatekeeper mutation. In the experiment, the researchers used many compounds, for example, rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3Safety of rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide).

rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (cas: 1035270-39-3) belongs to piperazine derivatives. Piperazine causes primary dermal irritation and skin burns at high concentrations. Piperazine also causes eye irritation in humans. Intermediate for a wide range of pharmaceuticals, polymers, dyes, corrosion inhibitors, rubber accelerators and surfactants.Safety of rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics