- Structure-based design of potent, amidine-derived inhibitors of factor Xa: Evaluation of selectivity, anticoagulant activity, and antithrombotic activity
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To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule I was docked into the act
- Wiley, Michael R.,Weir, Leonard C.,Briggs, Steven,Bryan, Nancy A.,Buben, John,Campbell, Charles,Chirgadze, Nickolay Y.,Conrad, Richard C.,Craft, Trelia J.,Ficorilli, James V.,Franciskovich, Jeffry B.,Froelich, Larry L.,Gifford-Moore, Donetta S.,Goodson Jr., Theodore,Herron, David K.,Klimkowski, Valentine J.,Kurz, Kenneth D.,Kyle, Jeffery A.,Masters, John J.,Ratz, Andrew M.,Milot, Guy,Shuman, Robert T.,Smith, Tommy,Smith, Gerald F.,Tebbe, Ann Louise,Tinsley, Jennifer M.,Towner, Richard D.,Wilson, Alexander,Yee, Ying K
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Read Online
- Copper-catalyzed regioselective 2-amination of o-haloanilides with aqueous ammonia
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An efficient Cu(II)-vasicine catalytic system has been developed for intramolecular C[sbnd]N bond formation. In this way, regioselective 2-amination of o-haloanilides with aqueous ammonia in EtOH has been achieved. This strategy provides several advantages, such as good regioselectivity, high yields and functional group tolerance.
- Tang, Yan-Ling,Li, Mei-Ling,Gao, Jin-Chun,Sun, Yun,Qu, Lu,Huang, Feng,Mao, Ze-Wei
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Read Online
- Buchwald-Hartwig amination of aryl esters and chlorides catalyzed by the dianisole-decorated Pd-NHC complex
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A modular and generic method for the Buchwald-Hartwig amination reactions of relatively unreactive aryl esters as acyl electrophiles and aryl chlorides as aryl electrophiles has been developed, leading to the efficient synthesis of amides/amines under air conditions and with low catalyst loadings. The success of this catalytic protocol is mainly attributed to the modification of the Pd-IPr skeleton with sterically hindered and electron-donating anisole groups. This method also features good functional group tolerance and excellent chemoselectivities. In summary, the results presented herein suggest the possibility of developing a versatile and general protocol for diverse electrophiles to undergo the Buchwald-Hartwig amination reactions, avoiding too much consideration of the reaction conditions for the substrate-dependent C-N bond formations.
- Zheng, Di-Zhong,Xiong, Hong-Gang,Song, A-Xiang,Yao, Hua-Gang,Xu, Chang
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supporting information
p. 2096 - 2101
(2022/04/01)
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- N-Acylbenzotriazole: convenient approach for protecting group-free monoacylation of symmetric diamines
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Abstract: An efficient green route for monoacylation of aromatic diamines, namely o-phenylenediamine and p-phenylenediamine and aliphatic diamines ethylenediamine and piperazine using N-acylbenzotriazoles (NABs) in n-butanol was developed. The new protocol does not require prior selective protection of the diamine and comprises simple conditions, short reaction times, an easy work up as well as high isolated yields (69–94%). Moreover, the method described herein enable stepwise acylation of aliphatic diamines such as ethylenediamine and piperazine with two different N-acylbenzotriazoles affording unsymmetrical substituted diamines that can be used for construction of pharmaceutically important targets such as drugs, foldamers, and drug conjugates. Graphic abstract: [Figure not available: see fulltext.]
- Agha, Khalid A.,Abo-Dya, Nader E.,Ibrahim, Tarek S.,Abdel-Aal, Eatedal H.,Abdel-Samii, Zakaria K.
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p. 589 - 598
(2020/05/06)
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- Folding Patterns in a Family of Oligoamide Foldamers
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A series of small, unsymmetrical pyridine-2,6-dicarboxylamide oligoamide foldamers with varying lengths and substituents at the end groups were synthetized to study their conformational properties and folding patterns. The @-type folding pattern resembled the oxyanion-hole motifs of enzymes, but several alternative folding patterns could also be characterized. Computational studies revealed several alternative conformers of nearly equal stability. These folding patterns differed from each other in their intramolecular hydrogen-bonding patterns and aryl-aryl interactions. In the solid state, the foldamers adopted either the globular @-type fold or the more extended S-type conformers, which were very similar to those foldamers obtained computationally. In some cases, the same foldamer molecule could even crystallize into two different folding patterns, thus confirming that the different folding patterns are very close in energy in spite of their completely different shapes. Finally, the best match for the observed NOE interactions in the liquid state was a conformation that matched the computationally characterized helix-type fold. Erase and refold: Like peptides, oligoamide foldamers fold into a number of different conformers that are very close in energy (see picture, stability energies in kcal mol-1 given in parentheses). By using a combination of computational, single-crystal X-ray diffraction, and NMR spectroscopic studies, these folding patterns have been identified and characterized for a family of seven different foldamers with varying substituents.
- Kortelainen, Minna,Suhonen, Aku,Hamza, Andrea,Pápai, Imre,Nauha, Elisa,Yliniemel?-Sipari, Sanna,Nissinen, Maija,Pihko, Petri M.
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supporting information
p. 9493 - 9504
(2015/06/30)
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- ANTIMICROBIAL COMPOUNDS
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The invention provides compounds for use in treating microbial infection in an animal. Example compounds include Pyridin-3-ylmethyl (4-((2-aminophenyl)- carbamoyl)benzyl)carbamate ("Entinostat"). The compounds can act via induction of the innate antimicrobial peptide defense system, and stimulation of autophagy.
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Page/Page column 33
(2015/05/19)
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- A journey from benzanilides to dithiobenzanilides: Synthesis of selective spasmolytic compounds
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A series of dithiobenzanilide derivatives was synthesized and each compound was evaluated for its ability to reduce KCl-induced contractions of smooth muscle preparations of the guinea pig. Starting from a recent publication describing benzanilide derivatives as antispasmodic agents, structure-activity guided synthesis was performed to obtain compounds with improved spasmolytic activity. First, compounds with two amide bonds were designed and second, both amide oxygens were replaced by two sp2 sulfur atoms resulting in dithiobenzanilide derivatives. The most potent antispasmodic dithiobenzanilide 19 showed improved activity with an IC50 value of 0.4 μM. Moreover, the study also demonstrated that these active compounds were able to antagonize the effect of spasmogens like acetylcholine and phenylephrine and that the activity is not mediated by activation of ATP-dependent potassium channels (KATP-channels) or inhibition of endothelial nitric oxide synthase (eNOS).
- Brunhofer, Gerda,Granig, Walter H.,Studenik, Christian R.,Erker, Thomas
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experimental part
p. 994 - 1001
(2011/03/18)
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- Expedient access to fused quinoxalines via Dess-Martin periodinane-mediated cyclization of unsymmetrical phenylenediamide derivatives
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One-pot cyclization of various 2-N-amido-homoallylanilides mediated by 4 equiv of Dess-Martin periodinane produced pyrrolo[1,2-a]quinoxalines (11 examples, up to 93% yield).
- Dobrotǎ, Cristian,Graeupner, Jonathan,Dumitru, Ioana,Matache, Mihaela,Paraschivescu, Codruta C.
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supporting information; experimental part
p. 1262 - 1264
(2010/04/29)
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- Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity
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Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 ? internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis-(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
- Moradei, Oscar M.,Mallais, Tammy C.,Frechette, Sylvie,Paquin, Isabelle,Tessier, Pierre E.,Leit, Silvana M.,Fournel, Marielle,Bonfils, Claire,Trachy-Bourget, Marie-Claude,Liu, Jianhong,Yan, Theresa P.,Lu, Ai-Hua,Rahil, Jubrail,Wang, James,Lefebvre, Sylvain,Li, Zuomei,Vaisburg, Arkadii F.,Besterman, Jeffrey M.
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p. 5543 - 5546
(2008/03/27)
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- Synthesis and biological activity of novel 1,2-disubstituted benzene derivatives as factor Xa inhibitors
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Factor Xa (fXa) is a serine protease that plays a pivotal role in the coagulation cascade. High-throughput screening of the Yamanouchi compound library yielded lead compound 1 with the ability to inhibit fXa at micromolar concentrations. To improve its fX
- Koshio, Hiroyuki,Hirayama, Fukushi,Ishihara, Tsukasa,Shiraki, Ryouta,Shigenaga, Takeshi,Taniuchi, Yuta,Sato, Kazuo,Moritani, Yumiko,Iwatsuki, Yoshiyuki,Kaku, Seiji,Katayama, Naoko,Kawasaki, Tomihisa,Matsumoto, Yuzo,Sakamoto, Shuichi,Tsukamoto, Shin-Ichi
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p. 1305 - 1323
(2007/10/03)
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- Benzimidazole compounds and their use as estrogen agonists/antagonists
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This invention relates to compounds, in particular benzimidazoles, that are useful as estrogen agonists and/or antagonists and pharmaceutical uses thereof. The present invention also relates to benzimidazoles that are selective for the ERβ receptor and pharmaceutical uses thereof.
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- BENZIMIDAZOLE COMPOUNDS AND THEIR USE AS ESTROGEN AGONISTS/ANTAGONISTS
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This invention relates to compounds, in particular benzimidazoles, that are useful as estrogen agonists and/or antagonists and pharmaceutical uses thereof. The present invention also relates to benzimidazoles that are selective for the ER? receptor and pharmaceutical uses thereof.
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- Antithrombotic agents
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This application relates to a compound of formula (I), a pharmaceutically acceptable salt of the compound, or a prodrug thereof, as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa, as well as a process for its
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