5408-04-8Relevant academic research and scientific papers
Metabotropic glutamate receptor 5 negative allosteric modulators: Discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1 H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases
Jaeschke, Georg,Kolczewski, Sabine,Spooren, Will,Vieira, Eric,Bitter-Stoll, Nadia,Boissin, Patrick,Borroni, Edilio,Büttelmann, Bernd,Ceccarelli, Simona,Clemann, Nicole,David, Beatrice,Funk, Christoph,Guba, Wolfgang,Harrison, Anthony,Hartung, Thomas,Honer, Michael,Huwyler, J?rg,Kuratli, Martin,Niederhauser, Urs,P?hler, Axel,Peters, Jens-Uwe,Petersen, Ann,Prinssen, Eric,Ricci, Antonio,Rueher, Daniel,Rueher, Marianne,Schneider, Manfred,Spurr, Paul,Stoll, Theodor,T?nnler, Daniel,Wichmann, Jürgen,Porter, Richard H.,Wettstein, Joseph G.,Lindemann, Lothar
, p. 1358 - 1371 (2015)
Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.
Synthesis of a Precursor of the Antiviral Agent A-315675
Egorov,Gimalova
, p. 241 - 244 (2019)
Ethyl 2-(acetylamino)-3-methoxy-3-methylhexanoate, a key precursor of the known pyrrolidine antiviral agent A-315675, was synthesized starting with the readily available acetoacetic ester.
Synthesis of deuterium-labeled 2-quinoxalinecarboxylic acid and 3-methylquinoxaline-2-carboxylic acid from deuterium aniline
Chen, Wulian,Zhao, Chaomin,Deng, Xiaojun
, p. 1043 - 1047 (2018)
An efficient and simple synthetic route of deuterium-labeled 2-quinoxalinecarboxylic acid-d4 (QCA-d4) and 3-methylquinoxaline-2-carboxylic acid-d4 (MQCA-d4) is presented with 99.9% and 99.6% isotopic enrichment using aniline-d5 as labeled starting material. Their chemical structures were confirmed by 1H NMR, and their isotopic abundance was determined by mass spectrometry analysis.
Switching a Xanthine Oxidase Inhibitor to a Dual-Target Antagonist of P2Y1and P2Y12as an Oral Antiplatelet Agent with a Wider Therapeutic Window in Rats than Ticagrelor
Lei, Yu,Zhang, Bing,Liu, Dan,Zhao, Jian,Dai, Xiwen,Gao, Jun,Mao, Qing,Feng, Yao,Zhao, Jiaxing,Lin, Fengwei,Duan, Yulin,Zhang, Yan,Bao, Ziyang,Yang, Yuwei,Mou, Yanhua,Wang, Shaojie
, p. 15752 - 15772 (2020)
ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y1 and P2Y12 on the platelet. The clinical effectiveness of inhibiting P2Y12 has been well established, and preclinical studies indicated that the inhibition of P2Y1 could provide equivalent antithrombotic efficacy as P2Y12 antagonists and reduce bleeding risks. On the basis of the 2-phenyl-1H-imidazole scaffold of our previously reported xanthine oxidase inhibitor WSJ-557, we first achieved the transition from the xanthine oxidase inhibitors to dual-target antagonists against P2Y1 and P2Y12. We described the structure-activity relationships of the 2-phenyl-1H-imidazole compounds, which led to the identification of the most potent antiplatelet agents, 24w and 25w, both showing a rapid onset of action in pharmacokinetic study. Furthermore, the rat model suggested that 24w demonstrated a wider therapeutic window than ticagrelor, displaying equivalent and dose-dependent antithrombotic efficacy with lower blood loss compared to ticagrelor at same oral dose. These results supported that 24w and 25w could be promising drug candidates.
Intracellular Distribution of Fluorescent Copper and Zinc Bis(thiosemicarbazonato) Complexes Measured with Fluorescence Lifetime Spectroscopy
Hickey, James L.,James, Janine L.,Henderson, Clare A.,Price, Katherine A.,Mot, Alexandra I.,Buncic, Gojko,Crouch, Peter J.,White, Jonathan M.,White, Anthony R.,Smith, Trevor A.,Donnelly, Paul S.
, p. 9556 - 9567 (2015)
The intracellular distribution of fluorescently labeled copper and zinc bis(thiosemicarbazonato) complexes was investigated in M17 neuroblastoma cells and primary cortical neurons with a view to providing insights into the neuroprotective activity of a copper bis(thiosemicarbazonato) complex known as CuII(atsm). Time-resolved fluorescence measurements allowed the identification of the CuII and ZnII complexes as well as the free ligand inside the cells by virtue of the distinct fluorescence lifetime of each species. Confocal fluorescent microscopy of cells treated with the fluorescent copper(II)bis(thiosemicarbazonato) complex revealed significant fluorescence associated with cytoplasmic puncta that were identified to be lysosomes in primary cortical neurons and both lipid droplets and lysosomes in M17 neuroblastoma cells. Fluorescence lifetime imaging microscopy confirmed that the fluorescence signal emanating from the lipid droplets could be attributed to the copper(II) complex but also that some degree of loss of the metal ion led to diffuse cytosolic fluorescence that could be attributed to the metal-free ligand. The accumulation of the copper(II) complex in lipid droplets could be relevant to the neuroprotective activity of CuII(atsm) in models of amyotrophic lateral sclerosis and Parkinson's disease.
Oxidation of: O -dioxime by (diacetoxyiodo)benzene: Green and mild access to furoxans
He, Chunlin,Pang, Siping,Zhang, Qi,Zhang, Xun,Zhao, Cheng
supporting information, p. 1489 - 1493 (2022/01/31)
Furoxan has been widely used in the field of high energy density materials because of its excellent properties such as high density, high standard enthalpy of formation and high nitrogen content. However, its existing synthesis methods are still restricted by the problems of difficult substrate preparation and manual handling of hazardous reagents. Herein, we disclosed a mild oxidation strategy to efficiently obtain furoxan derivatives starting from readily available o-dioxime substrates. This reaction features high functional group tolerance and easy scale-up, and has excellent regioselectivity for specific nonsymmetric o-dioximes. This method greatly reduces the safety risk and simplifies the operation process, and means that diversified furoxan derivatives can be easily accessed, thus paving the way for the wide application of furoxan derivatives. This journal is
From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase
Juillet, Charlotte,Ermolenko, Ludmila,Boyarskaya, Dina,Baratte, Blandine,Josselin, Béatrice,Nedev, Hristo,Bach, Stéphane,Iorga, Bogdan I.,Bignon, Jér?me,Ruchaud, Sandrine,Al-Mourabit, Ali
, p. 1197 - 1219 (2021/02/05)
Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F"and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.
Design, synthesis and biological evaluation of novel FXIa inhibitors with 2-phenyl-1H-imidazole-5-carboxamide moiety as P1 fragment
Lei, Yu,Zhang, Bing,Zhang, Yan,Dai, Xiwen,Duan, Yulin,Mao, Qing,Gao, Jun,Yang, Yuwei,Bao, Ziyang,Fu, Xuefeng,Ping, Kunqi,Yan, Chengda,Mou, Yanhua,Wang, Shaojie
, (2021/04/27)
Factor XIa, as a blood coagulation enzyme, amplifies the generation of the last enzyme thrombin in the blood coagulation cascade. It was proved that direct inhibition of factor XIa could reduce pathologic thrombus formation without an enhanced risk of bleeding. WSJ-557, a nonpurine imidazole-based xanthine oxidase inhibitor in our previous reports, could delay blood coagulation during its animal experiments, which prompted us to investigate its action mechanism. Subsequently, during the exploration of the action mechanism, it was found that WSJ-557 exhibited weak in vitro factor XIa binding affinity. Under the guide of molecular modeling, we adopted molecular hybridization strategy to develop novel factor XIa inhibitors with WSJ-557 as an initial compound. This led to the identification of the most potent compound 44g with a Ki value of 0.009 μM, which was close to that of BMS-724296 (Ki = 0.0015 μM). Additionally, serine protease selectivity study indicated that compound 44g display a desired selectivity, more 400-fold than those of thrombin, factor VIIa and factor Xa in coagulation cascade. Moreover, enzyme kinetics studies suggested that the representative compound 44g acted as a competitive-type inhibitor for FXIa, and molecular modeling revealed that it could tightly bind to the S1, S1′ and S2′ pockets of factor XIa. Furthermore, in vivo efficacy in the rabbit arteriovenous shunt model suggested that compound 44g demonstrated dose-dependent antithrombotic efficacy. Therefore, these results supported that compound 44g could be a potential and efficacious agent for the treatment of thrombotic diseases.
Lead optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series for the treatment of malaria
Kokkonda, Sreekanth,Deng, Xiaoyi,White, Karen L.,El Mazouni, Farah,White, John,Shackleford, David M.,Katneni, Kasiram,Chiu, Francis C. K.,Barker, Helena,Mclaren, Jenna,Crighton, Elly,Chen, Gong,Angulo-Barturen, Inigo,Jimenez-Diaz, Maria Belen,Ferrer, Santiago,Huertas-Valentin, Leticia,Martinez-Martinez, Maria Santos,Lafuente-Monasterio, Maria Jose,Chittimalla, Rajesh,Shahi, Shatrughan P.,Wittlin, Sergio,Waterson, David,Burrows, Jeremy N.,Matthews, Dave,Tomchick, Diana,Rathod, Pradipsinh K.,Palmer, Michael J.,Charman, Susan A.,Phillips, Margaret A.
, p. 4929 - 4956 (2020/06/08)
Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.
Sulfur-containing natural hinduchelins derivatives as potential antifungal agents against Rhizoctonia solani
Cao, Chunxia,Fang, Wei,Huang, Daye,Huang, Wenbo,Ke, Shaoyong,Shi, Liqiao,Wan, Zhongyi,Wang, Kaimei,Zhang, Zhigang
, (2020/05/18)
Aryl-oxazole alkaloids are an important class of heterocyclic natural products, and which has been demonstrated to exhibit broad biological functions. During the course of our research for highly active compounds from natural products, the natural hinduchelins A-D with typical aryl-oxazole unit have been synthesized and investigated. So, in order to develop highly potential functional molecules, a series of novel sulfur-containing aryl-oxazole compounds derived from natural hinduchelins was designed and synthesized, and their in vitro fungicidal activities against four common plant pathogenic fungi (oomycetes Phytophthora capsici, ascomycetes Sclerotinia sclerotiorum, deuteromycetes Botrytis cinerea and basidiomycetes Rhizoctonia solani) were evaluated, the results demonstrated that compounds 7b and 7c displayed good selectivity and specificity in vitro against basidiomycetes R. solani. In addition, the in vivo antifungal activities also indicated compounds 7b and 7c can protect the horsebean against infection by R. solani, and the possible mechanism of antifungal action for these compounds has also been investigated.
