5408-04-8Relevant articles and documents
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 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.
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
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.
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.
