Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor

Ruel, Réjean; Thibeault, Carl; L’Heureux, Alexandre; Martel, Alain; Cai, Zhen-Wei; Wei, Donna; Qian, Ligang; Barrish, Joel C.; Mathur, Arvind; D’Arienzo, Celia; Hunt, John T.; Kamath, Amrita V.; Marathe, Punit; Zhang, Yueping; Derbin, George; Wautlet, Barri; Mortillo, Steven; Jeyaseelan, Robert; Henley, Benjamin J.; Tejwani, Ravindra W.; Bhide, Rajeev S.; Trainor, George L.; Fargnoli, Joseph; Lombardo, Louis J.

doi:10.1016/j.bmcl.2008.03.057

Cited by 18 publications

(10 citation statements)

References 15 publications

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“…The most active derivative was compound 10 (BMS-645737) (Figure 4) which was also pre-clinically tested in vivo on various types of cancers in a heterogeneous model. It showed the highest anti-cancer activity for human lung cancer cells (L2987) [22].…”

Section: Anti-proliferative Effects Of 134-oxadiazole Derivativesmentioning

confidence: 99%

Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole

2018

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Compounds containing 1,3,4-oxadiazole ring in their structure are characterised by multidirectional biological activity. Their anti-proliferative effects associated with various mechanisms, such as inhibition of growth factors, enzymes, kinases and others, deserve attention. The activity of these compounds was tested on cell lines of various cancers. In most publications, the most active derivatives of 1,3,4-oxadiazole exceeded the effect of reference drugs, so they may become the main new anti-cancer drugs in the future.

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Section: Anti-proliferative Effects Of 134-oxadiazole Derivativesmentioning

confidence: 99%

Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole

2018

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“…The L-alanine prodrug of BMS-540215, BMS-582664 (75), was currently under evaluation in clinical trials for the treatment of solid tumors. A series of 7-azaindoles were also investigated as inhibitors of VEGFR-2 TK [48]. Biochemical potency and kinase selectivity optimization afford BMS-645737 (78) as antiangiogenic agent with good preclinical in vivo activity against human tumor xenograft models.…”

Section: Antiangiogenic Agents Of Triazine Typementioning

confidence: 99%

Recent Advances in Antiangiogenic Agents with VEGFR as Target

Zhang¹,

Shan²,

Pan³

et al. 2011

MRMC

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Angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. Its inhibition may be a valuable approach to cancer therapy. Antiangiogenic agents are designed to attack the tumor vasculature and cut off the tumor's supply of nutrients. Systemic blockade of angiogenesis has been recently approved for the treatment of several types of human cancers. Antiangiogenic therapy presents various advantages as compared to conventional treatment. Vascular endothelial growth factor (VEGF) is considered to be one of the most important regulators of angiogenesis and a key target in anticancer treatment. VEGF binding to its receptor (VEGFR) leads to cell proliferation and new vascular formation by tyrosine kinase (TK) pathway. VEGF/VEGFR pathway is becoming attractive target for anticancer drug design. It is believed to be important in the control of angiogenesis. Antiangiogenic therapy based on inhibition of VEGFR was reported to be powerful clinical strategies. In this review, the authors describe the existing literature regarding VEGFR inhibitors in the last few years. We attempt to cover all essential publications on the medicinal chemistry in terms of chemical structure, pharmacological profile and structure-activity relationships.

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“…Moreover, 1,3,4-Oxadiazole-2(3 H )-thiones, their thioether derivatives and 3-aminomethyl analogues ( N -Mannich bases) are the most interesting for their anticancer activities [ 21 , 22 ]. The 1,3,4-Oxadiazole derivatives exert their anticancer activities via different mechanisms, such as targeting epidermal growth factor receptors (EGFR) [ 23 ], vascular endothelial growth factor receptors (VEGF) [ 24 ], focal-adhesion kinase (FAK) [ 25 , 26 ], histone deacetylases (HDAC) [ 27 , 28 ], methionine aminopeptidase (MetAP) [ 29 ], NF-κB (nuclear factor κB) [ 30 ], poly(ADP-ribose) polymerase (PARP-1) [ 31 ], thymidine phosphorylase (TP) [ 32 ], telomerase [ 33 ], thymidylate synthase (TS) [ 34 ], zinc-finger protein 143 (ZNF143) [ 35 ], and tubulin polymerase [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

1,3,4-Oxadiazole N-Mannich Bases: Synthesis, Antimicrobial, and Anti-Proliferative Activities

et al. 2021

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The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a–l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a–d, respectively. The in vitro inhibitory activity of compounds 4a–l and 5a–d was assessed against pathogenic Gram-positive, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. The piperazinomethyl derivatives 5c and 5d displayed broad-spectrum antibacterial activities the minimal inhibitory concentration (MIC) 0.5–8 μg/mL) and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. In addition, the anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. The optimum anti-proliferative activity was attained by compounds 4l, 5a, 5c, and 5d.

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Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor

Cited by 18 publications

References 15 publications

Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole

Anti-Cancer Activity of Derivatives of 1,3,4-Oxadiazole

Recent Advances in Antiangiogenic Agents with VEGFR as Target

1,3,4-Oxadiazole N-Mannich Bases: Synthesis, Antimicrobial, and Anti-Proliferative Activities

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