- Palladium-catalyzed intermolecular C-H silylation initiated by aminopalladation
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A Pd(ii)-catalyzed intermolecular C-H silylation reaction initiated by aminopalladation has been developed. The C-H bonds were activated by an alkyl Pd(ii) species generated through aminopalladation and then disilylated with hexamethyldisilane to form disilylated indolines as the final products. The reaction provides a new method for the introduction of silyl groups into complex organic molecules.
- Ji, Xiaoming,Wei, Feng,Wan, Bin,Cheng, Cang,Zhang, Yanghui
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supporting information
p. 7801 - 7804
(2020/07/27)
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- Discovery and Evaluation of Pyrazolo[3,4-d]pyridazinone as a Potent and Orally Active Irreversible BTK Inhibitor
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The identification and lead optimization of a series of pyrazolo[3,4-d]pyridazinone derivatives are described as a novel class of potent irreversible BTK inhibitors, resulting in the discovery of compound 8. Compound 8 exhibited high potency against BTK kinase and acceptable PK profile. Furthermore, compound 8 demonstrated significant in vivo efficacy in a mouse-collagen-induced arthritis (CIA) model.
- Zhang, Xuejun,Sheng, Xijun,Shen, Jie,Zhang, Shoubo,Sun, Wenjie,Shen, Chunli,Li, Yi,Wang, Jun,Lv, Huqiang,Cui, Minghui,Zhu, Yuchuan,Huang, Lei,Hao, Dongling,Qi, Zhibo,Sun, Guanglong,Mao, Weifeng,Pan, Yan,Shen, Liang,Li, Xin,Hu, Guoping,Gong, Zhen,Han, Shuhua,Li, Jian,Chen, Shuhui,Tu, Ronghua,Wang, Xuehai,Wu, Chengde
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supporting information
p. 1863 - 1868
(2020/01/02)
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- 1-(1-Arylethylpiperidin-4-yl)thymine analogs as antimycobacterial TMPK inhibitors
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A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).
- Boshoff, Helena I. M.,Caljon, Guy,Forbes, He Eun,Hulpia, Fabian,Jian, Yanlin,Munier-Lehmann, Hélène,Risseeuw, Martijn D. P.,van Calenbergh, Serge
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- Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents
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Mycobacterium tuberculosis, the causative agent of tuberculosis, relies on thymidylate kinase (MtbTMPK) for the synthesis of thymidine triphosphates and thus also DNA synthesis. Therefore, this enzyme constitutes a potential Achilles heel of the pathogen. Based on a previously reported MtbTMPK 6-aryl-substituted pyridone inhibitor and guided by two co-crystal structures of MtbTMPK with pyridone- and thymine-based inhibitors, we report the synthesis of a series of aryl-shifted cyanopyridone analogues. These compounds generally lacked significant MtbTMPK inhibitory potency, but some analogues did exhibit promising antitubercular activity. Analogue 11i demonstrated a 10-fold increased antitubercular activity (MIC H37Rv, 1.2 μM) compared to literature compound 5. Many analogues with whole-cell antimycobacterial activity were devoid of significant cytotoxicity.
- Boshoff, Helena I. M.,Caljon, Guy,Forbes, He Eun,Hulpia, Fabian,Jian, Yanlin,Munier-Lehmann, Héle?ne,Risseeuw, Martijn D. P.,Van Calenbergh, Serge
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- BTK INHIBITOR
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Provided are a series of BTK inhibitors, and specifically disclosed are a compound, pharmaceutically acceptable salt thereof, tautomer thereof or prodrug thereof represented by formula (I), (II), (III) or (IV).
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Paragraph 0470-0471
(2017/11/16)
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- N-Substituted homopiperazine barbiturates as gelatinase inhibitors
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Matrix metalloproteinases are implicated in a wide range of pathophysiological processes and potent selective inhibitors for these enzymes continue to be eagerly sought. 5,5-Disubstituted barbiturates hold promise as inhibitor types being stable in vivo and relatively selective for the gelatinases (MMP-2 and MMP-9). In this paper we describe the synthesis of 5-piperazine and -homopiperazine substituted barbiturates. The activity of these compounds as gelatinase inhibitors was evaluated using supernatants from 12-O-tetradecanoylphorbol-13-acetate (PMA)-stimulated HT-1080 cells as well as using recombinant human MMPs. N-Acyl homopiperazine compounds were found to be potent inhibitors of the gelatinases (range in nM) and generally more potent than the corresponding piperazine analogues. The panel of N-acyl homopiperazines was enlarged in order to exploit differences between the gelatinases at the S2′ site in order to design MMP-2- or MMP-9-selective inhibitors. Compounds in this group exhibited single digit nano-molar potency and some selectivity between the two enzymes. Representative potent compounds were effective inhibitors of cancer cell migration.
- Wang, Jun,Medina, Carlos,Radomski, Marek W.,Gilmer, John F.
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experimental part
p. 4985 - 4999
(2011/10/04)
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- Novel benzimidazole derivatives as selective CB2 agonists
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The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1 nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.
- Pagé, Daniel,Balaux, Elise,Boisvert, Luc,Liu, Ziping,Milburn, Claire,Tremblay, Maxime,Wei, Zhongyong,Woo, Simon,Luo, Xuehong,Cheng, Yun-Xing,Yang, Hua,Srivastava, Sanjay,Zhou, Fei,Brown, William,Tomaszewski, Miroslaw,Walpole, Christopher,Hodzic, Leila,St-Onge, Stéphane,Godbout, Claude,Salois, Dominic,Payza, Keymal
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scheme or table
p. 3695 - 3700
(2009/04/04)
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- AGENT FOR CONTROLLING FUNCTION OF GPR34 RECEPTOR
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The present invention provides a GPR receptor function regulator comprising the compound represented by the formula: [wherein ring A is an optionally substituted isocyclic or heterocyclic ring, P is a bond or spacer, ring D is an optionally substituted monocyclic aromatic ring which may be condensed with a 5-to 7-membered ring, V is a bond or the group represented by the formula -CR14=CR15 - or - N=CR16- (wherein R14, R15 and R16 each represents a hydrogen atom or optionally substituted hydrocarbon group), Q is a bond or spacer, and W is a carboxyl or a group biologically equivalent to a carboxyl] or its salt or a prodrug thereof
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Page/Page column 139
(2010/11/28)
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- Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
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The present invention relates to compounds that are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action.
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Page/Page column 43
(2008/06/13)
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