2267-40-5Relevant articles and documents
Sulfamoylbenzamide-based Capsid Assembly Modulators for Selective Inhibition of Hepatitis B Viral Replication
Lee, Yeon Hee,Cha, Hyeon-Min,Hwang, Jun Yeon,Park, So Yeong,Vishakantegowda, Avinash G.,Imran, Ali,Lee, Joo-Youn,Yi, Yoon-Sun,Jun, Sangmi,Kim, Ga Hyeon,Kang, Hyo Jin,Chung, Sang J.,Kim, Meehyein,Kim, Hyejin,Han, Soo Bong
supporting information, p. 242 - 248 (2021/02/20)
As the spread of infections caused by hepatitis B virus (HBV) threatens public health worldwide, investigations from multiple perspectives and of various mechanisms of action are urgently required to increase the HBV cure rate. Targeting the encapsidation of the nuclear capsid protein (core protein, HBc) has emerged as an attractive strategy for inhibiting the viral assembly process; however, a drug targeting this mechanism has not yet been approved. We synthesized novel sulfamoylbenzamides (SBAs) as capsid assembly modulators of HBV and found that the effects and safety profiles of compounds 3 and 8 have potential therapeutic applicability against HBV. The formation of tubular particles was time-dependent in the presence of 3, indicating a new mode of protein assembly by SBA compounds. Our findings provide a new entity for developing safe and efficient treatments for HBV infection.
Design, synthesis and anti-HBV activity of NVR3-778 derivatives
Lv, Kai,Wu, Shuo,Li, Wenyan,Geng, Yunhe,Wu, Meng,Zhou, Jinming,Li, Yuhuan,Gao, Qiang,Liu, Mingliang
, (2019/11/13)
NVR3-778, one of the most advanced capsid assembly modulators (CAMs), is currently in phase II clinical trial for the treatment of HBV infection. In this study, we reported the first structure optimization of NVR3-778. Compound 2d was found to exhibit more potent anti-HBV activity (IC50: 0.25 μM), lower cytotoxicity (CC50: 10.68 μM) and higher selectivity index (SI: 40.72) than NVR3-778 (IC50: 0.33 μM; CC50: 5.14 μM; SI: 18.36) in vitro, and also display similar inhibitory effect on the assembly of HBV capsids as NVR3-778. Molecular docking further suggested that compound 2d might form a stronger interaction with core protein. Moreover, compound 2d also showed acceptable pharmacokinetic profiles. Currently compound 2d was selected as a new lead for further modifications, and studies to determine the in vivo anti-HBV studies of 2d will begin soon.
Synthesis of a new series of 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides as carbonic anhydrase I, II, IV and IX inhibitors
Swain, Baijayantimala,Angeli, Andrea,Angapelly, Srinivas,Thacker, Pavitra S.,Singh, Priti,Supuran, Claudiu T.,Arifuddin, Mohammed
, p. 1199 - 1209 (2019/07/02)
The synthesis of a novel series of 3-functionalised benzenesulfonamides incorporating phenyl-1,2,3-triazole with an amide linker was achieved by using the “click-tail” approach. The new compounds, including the intermediates, were assayed as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isoforms) and also for hCA IV and IX (transmembrane isoforms) taking acetazolamide as standard drug. Most of these compounds exhibited excellent activity against all these isoforms. hCA I was inhibited with Kis in the range of 50.8–966.8 nM, while the glaucoma associated hCA II was inhibited with Kis in the range of 6.5–760.0 nM. Isoform hCA IV was inhibited with Kis in the range of 65.3–957.5 nM, whereas the tumor associated hypoxia induced hCA IX was inhibited with Kis in the range of 30.8–815.9 nM. The structure activity relationship study for the 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides against these isoforms was also inferred from the results.
Synthesis and Biological Evaluation of 4-Sulfamoylphenyl/Sulfocoumarin Carboxamides as Selective Inhibitors of Carbonic Anhydrase Isoforms hCA II, IX, and XII
Angapelly, Srinivas,Angeli, Andrea,Khan, Arbaj Jabbar,Sri Ramya,Supuran, Claudiu T.,Arifuddin, Mohammed
, p. 1165 - 1171 (2018/05/30)
With the aim to develop potent and selective human carbonic anhydrase inhibitors (hCAIs), we synthesized 4-sulfamoylphenyl/sulfocoumarin benzamides (series 5 a–r and series 7 a–q) and evaluated their inhibition profiles against five isoforms of the zinc-containing human carbonic anhydrase (hCA, EC 4.2.1.1): cytosolic hCA I and II, and the transmembrane isozymes hCA IV, IX, and XII. Compounds 5 a–r were found to selectively inhibit hCA II in the nanomolar range, while being less effective against the other hCA isoforms. As noted from the literature, sulfocoumarin (1,2-benzoxathiine 2,2-dioxide) acts as a “prodrug” inhibitor and is hydrolyzed by the esterase activity of hCA to form 2-hydroxyphenylvinylsulfonic acid, which thereafter binds to the enzyme in a manner similar to that of coumarins and sulfoxocoumarins. All these sulfocoumarins (compounds 7 a–q) were found to be very weak or ineffective as inhibitors of the housekeeping off-target hCA isoforms I and II, and effectively inhibited the transmembrane tumor-associated isoforms IX and XII in the high nanomolar to micromolar ranges. Further structural modifications of these molecules could be useful for the development of effective hCA inhibitors used for the treatment of glaucoma, epilepsy, and cancer.
Small Molecule Microarray Based Discovery of PARP14 Inhibitors
Peng, Bo,Thorsell, Ann-Gerd,Karlberg, Tobias,Schüler, Herwig,Yao, Shao Q.
supporting information, p. 248 - 253 (2016/12/30)
Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1. Co-crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure–activity relationship studies identified important binding elements in the adenine subsite. In tumor cells, H10 was able to chemically knockdown endogenous PARP14 activities.
HEPATITIS B VIRAL ASSEMBLY EFFECTORS
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Paragraph 00214, (2016/10/31)
Novel assembly effector compounds having a therapeutic effect against hepatitis B viral (HBV) infection are disclosed. Assembly effector molecules described herein can lead to defective viral assembly and also may affect other viral activities associated with chronic HBV infection. Also disclosed is a process to synthesize disclosed compounds, method of treatment of HBV by administration of disclosed compounds, and use of these compounds in the manufacture of medicaments against HBV.
Design, synthesis, and pharmacological evaluation of highly potent and selective dipeptidyl peptidase-4 inhibitors
Jiang, Tao,Zhou, Yuren,Zhu, Jianming,Chen, Zhuxi,Sun, Peng,Zhang, Qiang,Wang, Zhen,Shao, Qiang,Jiang, Xiangrui,Li, Bo,Wang, Heyao,Zhu, Weiliang,Shen, Jingshan
, p. 399 - 407 (2015/06/08)
The optimization of a series of fused β-homophenylalanine inhibitors of dipeptidyl peptidase-4 (DPP-4) is described. Modification on the P2-binding moiety of 6 (IC50 = 10 nM) led to the discovery of β-homophenylalanine derivatives containing pyrrolidin-2-ylmethyl amides. The introduction of a sulfamine in the meta position of the phenyl ring improved the potency against DPP-4 (6-12-fold increase). Compound 14k showed DPP-4 inhibitory activity with an IC50 value of 0.87 nM. Meanwhile, in vivo experiments exhibited that 14h had an efficiency comparable to sitagliptin at the dose of 10 mg/kg.
GLYCOSIDE DERIVATIVES AND USES THEREOF
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Page/Page column 54, (2010/04/25)
The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts, to formulations and uses in the treatment of, interalia, metabolic disorders.
ARYLSULFONAMIDE-BASED MATRIX METALLOPROTEASE INHIBITORS
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Page/Page column 42-43, (2009/10/22)
The present invention provides a compound of formula (I):said compound is inhibitor of MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12 and/or MMP-13, and thus can be employed for the treatment of a disorder or disease characterized by abnormal activity of MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12 and/or MMP- 13. Accordingly, the compound of formula (I) can be used in treatment of disorders or diseases mediated by MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12, and/or MMP- 13. Finally, the present invention also provides a pharmaceutical composition.
Structure-based design, synthesis, and study of potent inhibitors of β-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents
Nie, Zhe,Perretta, Carin,Lu, Jia,Su, Ying,Margosiak, Stephen,Gajiwala, Ketan S.,Cortez, Joseph,Nikulin, Victor,Yager, Kraig M.,Appelt, Krzysztof,Chu, Shaosong
, p. 1596 - 1609 (2007/10/03)
Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, β-ketoacyl-ACP synthase III, is a particularly attractiv
