170859-70-8Relevant articles and documents
Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-β-lactamase inhibitors
Yan, Yu-Hang,Li, Wenfang,Chen, Wei,Li, Chao,Zhu, Kai-Rong,Deng, Ji,Dai, Qing-Qing,Yang, Ling-Ling,Wang, Zhenling,Li, Guo-Bo
, (2021/11/17)
Production of metallo-β-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the ‘last-resort’ carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance.
Palladium-catalyzed regioselective allylation of five-membered heteroarenes with allyltributylstannane
Zhang, Sheng,Yu, Xiaoqiang,Feng, Xiujuan,Yamamoto, Yoshinori,Bao, Ming
supporting information, p. 3842 - 3845 (2015/03/30)
Palladium-catalyzed allylation reactions of 2-(chloromethyl)thiophenes, 2-(chloromethyl)furans, and N-protected 2-(chloromethyl)-1H-pyrroles with allyltributylstannane were described in this study. This type of allylation reaction regioselectively occurred on the heteroarene rings to produce allylated dearomatization products or allylated heteroarenes with satisfactory yields.
SUBSTITUTED 2-AZA-BICYCLO[2.2.1]HEPTANE-3-CARBOXYLIC ACID (CYANO-METHYL)-AMIDES INHIBITORS OF CATHEPSIN C
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Page/Page column 70; 71; 72, (2014/09/29)
This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (cyano-methyl)-amides of formula (1) and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.
Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1 (BACE1) inhibitors: Conformational constraint to favor a bioactive conformation
Mandal, Mihirbaran,Zhu, Zhaoning,Cumming, Jared N.,Liu, Xiaoxiang,Strickland, Corey,Mazzola, Robert D.,Caldwell, John P.,Leach, Prescott,Grzelak, Michael,Hyde, Lynn,Zhang, Qi,Terracina, Giuseppe,Zhang, Lili,Chen, Xia,Kuvelkar, Reshma,Kennedy, Matthew E.,Favreau, Leonard,Cox, Kathleen,Orth, Peter,Buevich, Alexei,Voigt, Johannes,Wang, Hongwu,Kazakevich, Irina,McKittrick, Brian A.,Greenlee, William,Parker, Eric M.,Stamford, Andrew W.
, p. 9331 - 9345 (2013/01/15)
On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2′ binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2′. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Aβ40 in the plasma, CSF, and cortex of rats in a dose-dependent manner.
NOVEL HETEROCYCLIC ACRYLAMIDES AND THEIR USE AS PHARMACEUTICALS
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Page/Page column 142, (2011/06/19)
The invention relates to novel heterocyclic acrylamide compounds (I), to the preparation of the compounds and intermediates used therein, to the use of the compounds as antibacterial medicaments and pharmaceutical compositions containing the compounds.
THIOPHENYL-SUBSTITUTED 2-IMINO-3-METHYL PYRROLO PYRIMIDINONE COMPOUNDS AS BACE-1 INHIBITORS, COMPOSITIONS, AND THEIR USE
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Page/Page column 91, (2009/12/05)
In its many embodiments, the present invention provides provides certain thiophenyl-substituted 2-imino-3-methyl pyrrolo pyrimidone compounds, including compounds (or tautomers or a pharmaceutically acceptable salts thereof) having the structural Formula (III): wherein R2, R3, R4, R5, R6, R7, R8, and R9 are each selected independently and as defined herein. Pharmaceutical compositions comprising one or more such compounds, and methods for their preparation and use in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimer's Disease, are also disclosed.
Theory-guided design and synthesis of multichromophore dendrimers: An analysis of the electro-optic effect
Sullivan, Philip A.,Rommel, Harrison,Liao, Yi,Olbricht, Benjamin C.,Akelaitis, Andrew J. P.,Firestone, Kimberly A.,Kang, Jae-Wook,Luo, Jingdong,Davies, Joshua A.,Dong, Hoon Choi,Eichinger, Bruce E.,Reid, Philip J.,Chen, Antao,Jen, Alex K.-Y.,Robinson, Bruce H.,Dalton, Larry R.
, p. 7523 - 7530 (2008/02/09)
Extensive experimental and theoretical study suggests that interchromophore electrostatic interactions are among the most severe impediments to the induction and stability of large electro-optic coefficients in electric-field-poled organic materials. In t
ASPARTYL PROTEASE INHIBITORS
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Page/Page column 45-46, (2008/06/13)
Disclosed are compounds of the formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein j, k, U, W, R, R1, R2, R3, R4, R6, R7 and R7a are as described above in the specification. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula (I) in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.
