- Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
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Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
- Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
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p. 4623 - 4661
(2021/05/07)
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- Probing 2H-Indazoles as Templates for SGK1, Tie2, and SRC Kinase Inhibitors
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The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2-substituted aza-2H-indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so-far underrepresented aza-2H-indazole scaffold, indazoles were connected at the N2 position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A synthesized focused library of 52 different aza-2H-indazole derivatives showed good initial selective inhibition against SGK1, Tie2, and SRC kinases, with the best representatives having IC50 values in the range of 500 nm. In a comparative computational study, these data were analyzed and rationalized in light of docking studies.
- Schoene, Jens,Gazzi, Thais,Lindemann, Peter,Christmann, Mathias,Volkamer, Andrea,Nazaré, Marc
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p. 1514 - 1527
(2019/08/07)
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- 5-SULFAMOYL-2-HYDROXYBENZAMIDE DERIVATIVES
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The invention is directed to substituted salicylamide derivatives. Specifically, the invention is directed to compounds according to Formula (I): wherein R, R1 and R2 are as defined herein, or a pharmaceutically acceptable salt thereof. The compounds of the invention are inhibitors of CD73 and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with CD73 inhibition, such as AIDS, the treatment of HIV, autoimmune diseases, infections, atherosclerosis, and ischemia–reperfusion injury. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting CD73 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 127
(2017/09/27)
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- Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors
-
We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity.
- Elgaher, Walid A. M.,Sharma, Kamal K.,Haupenthal, J?rg,Saladini, Francesco,Pires, Manuel,Real, Eleonore,Mély, Yves,Hartmann, Rolf W.
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supporting information
p. 7212 - 7222
(2016/08/24)
-
- HEPARAN SULFATE BIOSYNTHESIS INHIBITORS FOR THE TREATMENT OF DISEASES
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Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions in need of inhibition of heparan sulfate biosynthesis.
- -
-
Paragraph 000790
(2016/05/02)
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- Boron trifluoride-methanol complex. Mild and powerful reagent for deprotection of acetylated amines. Scope and selectivity
-
A boron trifluoride-methanol complex demonstrated remarkable deprotection selectivity against commonly used amino-protecting groups in the deacetylation of acetanilides and high sensitivity to the steric hindrance of substrates. The scope and limitations of the reaction were explored.
- Miltsov, Sergey,Karavan, Vladimir,Misharev, Alexandr,Alonso-Chamarro, Julian,Puyol, Mar
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supporting information
p. 641 - 644
(2016/01/26)
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- BIFUNCTIONAL COMPOUNDS AND USE FOR REDUCING URIC ACID LEVELS
-
Bifunctional compounds that increase uric acid excretion and reduce uric acid production, and monofunctional compounds that either increase uric acid excretion or reduce uric acid production. Methods of using these compounds for reducing uric acid levels
- -
-
Paragraph 00119
(2016/12/22)
-
- Pyrrole inhibitors of S-nitrosoglutathione reductase as therapeutic agents
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The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
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-
Page/Page column 299-300
(2015/11/16)
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- SUBSTITUTED TRICYCLIC COMPOUNDS WITH ACTIVITY TOWARDS EP1 RECEPTORS
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The present invention belongs to the field of EP1 receptor ligands. More specifically it refers to compounds of general formula (I) having great affinity and selectivity for the EP1 receptor. The invention also refers to the process for their preparation, to their use as medicament for the treatment and/or prophylaxis of diseases or disorders mediated by the EP1 receptor as well as to pharmaceutical compositions comprising them.
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Page/Page column 45
(2013/10/22)
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- Structure-activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: Carboxamide modification
-
The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, gastrointestinal, and cardiovascular systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development for acute asthma. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety. We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice.
- Sun, Xicheng,Qiu, Jian,Strong, Sarah A.,Green, Louis S.,Wasley, Jan W.F.,Blonder, Joan P.,Colagiovanni, Dorothy B.,Stout, Adam M.,Mutka, Sarah C.,Richards, Jane P.,Rosenthal, Gary J.
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supporting information; experimental part
p. 2338 - 2342
(2012/04/18)
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- SUBSTITUTED 8 - AMINO - IMIDAZO [1, 2-A] PYRAZ1NES AS ANTIBACTERIAL AGENTS
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The present invention relates to substituted imidazo[1,2-a]pyrazines of Formula (I) and their use as antibacterial agents.
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-
Page/Page column 93-94
(2013/02/27)
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- Efficient large-scale synthesis of 2-amino-5- methanesulfonylaminobenzenesulfonamide
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A novel synthesis of 2-amino-5-methanesulfonylaminobenzenesulfonamide is described. This preparation begins with readily available 4-nitroaniline and proceeds through five steps (isolations) in 41% overall yield. The described chemistry is conducted on a 50- to 100-g scale and does not require extractive workup procedures or chromatographic purifications. Copyright Taylor & Francis Group, LLC.
- Dragovich, Peter S.,Murphy, Douglas E.,Tran, Chinh V.,Ruebsam, Frank
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p. 1909 - 1916
(2008/09/20)
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- 5,6-DIHYDRO-1H-PYRIDIN-2-ONE COMPOUNDS
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The invention is directed to 5,6-dihydro-1H-pyridin-2-one compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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Page/Page column 66
(2008/12/06)
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- PYRIDAZINONE COMPOUNDS
-
The invention is directed to pyridazinone compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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-
Page/Page column 168-169
(2008/12/07)
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- PYRIDAZINONE COMPOUNDS
-
The invention is directed to pyridazinone compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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-
Page/Page column 24
(2008/12/07)
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- PYRRO[1,2-B]PYRIDAZINONE COMPOUNDS
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The invention is directed to pyrro[l,2-b]pyridazinone compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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Page/Page column 48; 70
(2008/06/13)
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- Analysis of structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]thiourea analogues as TRPV1 antagonists
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The structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. The 2-halogen analogues showed enhanced antagonism compared to the prototype antagonist.
- Lee, Jeewoo,Kang, Sang-Uk,Kil, Min-Jung,Shin, Myoungyoup,Lim, Ju-Ok,Choi, Hyun-Kyung,Jin, Mi-Kyoung,Kim, Su Yeon,Kim, Sung-Eun,Lee, Yong-Sil,Min, Kyung-Hoon,Kim, Young-Ho,Ha, Hee-Jin,Tran, Richard,Welter, Jacqueline D.,Wang, Yun,Szabo, Tamas,Pearce, Larry V.,Lundberg, Daniel J.,Toth, Attila,Pavlyukovets, Vladimir A.,Morgan, Matthew A.,Blumberg, Peter M.
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p. 4136 - 4142
(2007/10/03)
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- Analysis of structure-activity relationships with the N-(3-acyloxy-2- benzylpropyl)-N′-[4-(methylsulfonylamino)benzyl]thiourea template for vanilloid receptor 1 antagonism
-
In a continuing effort to elucidate the structure-activity relationships of the lead antagonist N-[2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl]-N ′-[4-(methylsulfonylamino)benzyl]thiourea (1), the distances between the proposed four pharmacophores in 1 have been varied by insertion or deletion of one carbon to optimize their fit to the receptor. In addition, the acyloxy group of the C region was replaced with amide and N-hydroxy amide to identify the pharmacophoric importance of the ester group in the C2 region. The results indicated that the pharmacophoric arrangement of 1 was optimal for receptor binding affinity and antagonism, and the ester of the C2 region was significant for receptor binding. Among the derivatives, compound 19 showed distinct behavior with a 2-fold improvement in antagonism but a 13-fold reduction in binding affinity compared to 1. The partial separation of pharmacophoric requirements of these two assays has been noted before and compound 19 is thus selective for the calcium entry-linked receptor population. The conformational analysis of 1 generated three distinct conformers having different types of hydrophobic interactions, which will be utilized for exploring the active conformation of the VR1 ligand.
- Lee, Jeewoo,Kim, Su Yeon,Lee, Jiyoun,Kang, Myungsim,Kil, Min-Jung,Choi, Hyun-Kyung,Jin, Mi-Kyung,Wang, Yun,Toth, Attila,Pearce, Larry V.,Lundberg, Daniel J.,Tran, Richard,Blumberg, Peter M.
-
p. 3411 - 3420
(2007/10/03)
-
- SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL N-1-ARYL-6-FLUORO-5-METHYL-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACIDS
-
A series of 5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acids was prepared in which the N-1 position was substituted by various aryl groups.Seven compounds showed excellent in vitro antibacterial activity against Gram-positive and Gram-negative strains.
- Jacquet, Jean-Pierre,Bouzard, Daniel,Cesare, Pierre Di,Dolnic, Nicolas,Massoudi, Massoud,Remuzon, Philippe
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p. 2301 - 2311
(2007/10/02)
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- QUINONE-IMIDES : REGIOSPECIFICITY OF NUCLEOPHILIC ATTACK ON N-ALKANESULPHONYL-N'-ALKANOYL 1,4-BENZOQUINONE-IMINES.
-
Substrates such as (2) undergo regiospecific attack by azide and thiocyanate ions at the terminus of the C=C-C=N-CO system.In the case of addition of azide, this is proved by the detailed analysis of the 1H and 13C NMR spectra of the products (11) derived from the quinone-imides (8).The structure of the products obtained by the addition of thiocyanate to the quinone-imides (10) and (20) is proved by their facile cyclisation to the 2-aminobenzothiazoles (18) and (21) respectively.
- Rajappa, Srinivasaschari,Shenoy, Sharada J.
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p. 5739 - 5746
(2007/10/02)
-
- Substituent effects in infrared spectroscopy-VII. Meta and para substituted methanesulphonanilides
-
Substituent effects on the NH frequencies of the conformers of methanesulphonanilides, their cyclic dimers and their hydrogen bonded complexes with acetonitrile have been analysed by means of the Hammet equation.An electron-withdrawing substituent may either increase or decrease ν(NH) in the XC6H4NHY series according to the electronic nature of the Y group.This can be explained by the non-monotonic dependence of the NH stretching frequency on the ionic character of the NH bond.
- Laurence, C.,Berthelot, M.,Lucon, M.,Tsuno, Y.
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p. 791 - 796
(2007/10/02)
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