- 1,2,4-Triazole-3-Thione Analogues with a 2-Ethylbenzoic Acid at Position 4 as VIM-type Metallo-β-Lactamase Inhibitors
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Metallo-β-lactamases (MBLs) are increasingly involved as a major mechanism of resistance to carbapenems in relevant opportunistic Gram-negative pathogens. Unfortunately, clinically efficient MBL inhibitors still represent an unmet medical need. We previou
- Benvenuti, Manuela,Bouajila, Ezeddine,Cerboni, Giulia,Chelini, Giulia,Corsica, Giuseppina,De Luca, Filomena,Docquier, Jean-Denis,Feller, Georges,Galleni, Moreno,Gavara, Laurent,Hernandez, Jean-Fran?ois,Legru, Alice,Licznar-Fajardo, Patricia,Mangani, Stefano,Mercuri, Paola Sandra,Pozzi, Cecilia,Sannio, Filomena,Sevaille, Laurent,Tanfoni, Silvia,Tassone, Giusy,Verdirosa, Federica,Vo Hoang, Yen
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- HETEROCYCLIC WDR5 INHIBITORS AS ANTI-CANCER COMPOUNDS
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The present invention provides compounds of Formula (I) or a pharmaceutically acceptable salt thereof; (I) which are inhibitors of WDR5. The present invention also provides pharmaceutical compositions comprising such compounds, compositions comprising such compounds with an additional therapeutic agent and the therapeutic uses of such compounds.
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Page/Page column 76-77
(2021/02/19)
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- INHIBITORS OF FIBROBLAST ACTIVATION PROTEIN
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Compounds and compositions for modulating fibroblast activation protein (FAP) are described. The compounds and compositions may find use as therapeutic agents for the treatment of diseases, including hyperproliferative diseases.
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Paragraph 0265
(2020/07/14)
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- WDR5 INHIBITORS AND MODULATORS
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Isoquinolinone compounds and derivatives inhibit WDR5 and associated protein-protein interactions, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject, such as cancer cell proliferation.
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Paragraph 0119
(2020/06/10)
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- Catalyst-free cyclization of anthranils and cyclic amines: One-step synthesis of rutaecarpine
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An efficient synthesis of a variety of quinazolinone derivatives via a direct cyclization reaction between commercially available anthranils and cyclic amines is described. The developed transformation proceeds with the merits of high step- and atom-efficiency, a broad substrate scope, and good to excellent yields, without additional catalysts, and offers a practical way for the preparation of rutaecarpine and its derivatives with structural diversity.
- Li, Jian,Wang, Zheng-Bing,Xu, Yue,Lu, Xue-Chen,Zhu, Shang-Rong,Liu, Li
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p. 12072 - 12075
(2019/10/14)
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- ASK1 INHIBITOR AND PREPARATION METHOD AND USE THEREOF
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The present disclosure relates to a compound as shown in formula (II), a tautomer or a pharmaceutically acceptable salt thereof, and disclosed is the use thereof in preparing a drug for treating an ASK1-associated disease.
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- Facile synthesis of 5-To 7-membered benzolactam compounds via strongly facilitated electrophilic aromtic substitution reaction
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We employed our system to activate aromatic ring-Tethered carbamate compounds with trifluoromethanesulfonic acid to obtain benzolactams with 5-To 7-membered rings, and examined the substrate scope and limitations of this activation method. In 5-membered ring formation, a halogen group on the aromatic ring did not greatly affect the reaction yield, but other electron-donating groups inhibited the cyclization reaction, and various side-reactions occurred. In 7-membered ring formation, eletron-donating groups on aromatic ring promoted the cyclization reaction, but cyclization of electron-deficient aromatic rings did not proceed well. The 6-membered ring formation reaction showed the greatest substrate generality.
- Kurouchi, Hiroaki,Otani, Yuko,Ohwada, Tomohiko
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p. 705 - 713
(2017/04/10)
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- Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties
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Late sodium current (late INa) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Nav 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late INa inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late INa inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.
- Zablocki, Jeff A.,Elzein, Elfatih,Li, Xiaofen,Koltun, Dmitry O.,Parkhill, Eric Q.,Kobayashi, Tetsuya,Martinez, Ruben,Corkey, Britton,Jiang, Haibo,Perry, Thao,Kalla, Rao,Notte, Gregory T.,Saunders, Oliver,Graupe, Michael,Lu, Yafan,Venkataramani, Chandru,Guerrero, Juan,Perry, Jason,Osier, Mark,Strickley, Robert,Liu, Gongxin,Wang, Wei-Qun,Hu, Lufei,Li, Xiao-Jun,El-Bizri, Nesrine,Hirakawa, Ryoko,Kahlig, Kris,Xie, Cheng,Li, Cindy Hong,Dhalla, Arvinder K.,Rajamani, Sridharan,Mollova, Nevena,Soohoo, Daniel,Lepist, Eve-Irene,Murray, Bernard,Rhodes, Gerry,Belardinelli, Luiz,Desai, Manoj C.
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p. 9005 - 9017
(2016/10/22)
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- Protonation switching to the least-basic heteroatom of carbamate through cationic hydrogen bonding promotes the formation of isocyanate cations
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We found that phenethylcarbamates that bear ortho-salicylate as an ether group (carbamoyl salicylates) dramatically accelerate O-C bond dissociation in strong acid to facilitate generation of isocyanate cation (N-protonated isocyanates), which undergo subsequent intramolecular aromatic electrophilic cyclization to give dihydroisoquinolones. To generate isocyanate cations from carbamates in acidic media as electrophiles for aromatic substitution, protonation at the ether oxygen, the least basic heteroatom, is essential to promote C-O bond cleavage. However, the carbonyl oxygen of carbamates, the most basic site, is protonated exclusively in strong acids. We found that the protonation site can be shifted to an alternative basic atom by linking methyl salicylate to the ether oxygen of carbamate. The methyl ester oxygen ortho to the phenolic (ether) oxygen of salicylate is as basic as the carbamate carbonyl oxygen, and we found that monoprotonation at the methyl ester oxygen in strong acid resulted in the formation of an intramolecular cationic hydrogen bond (>C=O+-H...O) with the phenolic ether oxygen. This facilitates O-C bond dissociation of phenethylcarbamates, thereby promoting isocyanate cation formation. In contrast, superacid-mediated diprotonation at the methyl ester oxygen of the salicylate and the carbonyl oxygen of the carbamate afforded a rather stable dication, which did not readily undergo C-O bond dissociation. This is an unprecedented and unknown case in which the monocation has greater reactivity than the dication.
- Kurouchi, Hiroaki,Sumita, Akinari,Otani, Yuko,Ohwada, Tomohiko
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supporting information
p. 8682 - 8690
(2014/07/21)
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- 17a-HYDROXYLASE/C17,20-LYASE INHIBITORS
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
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Paragraph 0202
(2014/03/21)
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- Exploration of a series of 5-arylidene-2-thioxoimidazolidin-4-ones as inhibitors of the cytolytic protein perforin
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A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perforin. Structure-activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations (≤2.5 μM) by surface plasmon resonance and prevented formation of perforin pores in target cells despite effective target cell engagement, as determined by calcium influx studies. Mouse PK studies of two analogues showed T1/2 values of 1.1-1.2 h (dose of 5 mg/kg iv) and MTDs of 60-80 mg/kg (ip).
- Spicer, Julie A.,Lena, Gersande,Lyons, Dani M.,Huttunen, Kristiina M.,Miller, Christian K.,O'Connor, Patrick D.,Bull, Matthew,Helsby, Nuala,Jamieson, Stephen M. F.,Denny, William A.,Ciccone, Annette,Browne, Kylie A.,Lopez, Jamie A.,Rudd-Schmidt, Jesse,Voskoboinik, Ilia,Trapani, Joseph A.
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supporting information
p. 9542 - 9555
(2014/01/06)
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- 2-(Pyrrolidin-1-yl)ethyl-3,4-dihydroisoquinolin-1(2H)-one derivatives as potent and selective histamine-3 receptor antagonists
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On the basis of the previously reported benzimidazole 1,3′- bipyrrolidine benzamides (1), a new class of 2-(pyrrolidin-1-yl)ethyl-3,4- dihydroisoquinolin-1(2H)-one derivatives (3-50) were synthesized and evaluated as potent H3 receptor antagonists. In particular, compound 39 exhibited potent in vitro binding and functional activities at the H3 receptor, good selectivities against other neurotransmitter receptors and ion channels, acceptable pharmacokinetic properties, and a favorable in vivo profile.
- Zhou, Dahui,Gross, Jonathan L.,Adedoyin, Adedayo B.,Aschmies, Suzan B.,Brennan, Julie,Bowlby, Mark,Di, Li,Kubek, Katie,Platt, Brian J.,Wang, Zheng,Zhang, Guoming,Brandon, Nicholas,Comery, Thomas A.,Robichaud, Albert J.
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experimental part
p. 2452 - 2468
(2012/05/05)
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- 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
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Page/Page column 39
(2012/04/04)
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- Identification of non-amidine inhibitors of acid-sensing ion channel-3 (ASIC3)
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A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3
- Kuduk, Scott D.,Chang, Ronald K.,Di Marco, Christina N.,Dipardo, Robert M.,Cook, Sean P.,Cato, Matthew J.,Jovanovska, Aneta,Urban, Mark O.,Leitl, Michael,Spencer, Robert H.,Kane, Stefanie A.,Hartman, George D.,Bilodeau, Mark T.
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p. 4255 - 4258
(2011/08/10)
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- COMPOUNDS, PREPARATIONS AND USES THEREOF
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The present invention provides novel compounds of the Formula (I), pharmaceutical compositions comprising such compounds and methods for using such compounds as agents or drugs for inhibiting perforin activity and for treating a subject at risk of or susc
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Page/Page column 125
(2011/07/09)
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- CARBAZOLE CARBOXAMIDE COMPOUNDS USEFUL AS KINASE INHIBITORS
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Compounds having the formula (I), and enantiomers, and diastereomers, pharmaceutically-acceptable salts, thereof, are useful as kinase modulators, including Btk modulation.
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Page/Page column 36
(2010/07/04)
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- ISOQUINOLINYL AND ISOINDOLINYL DERIVATIVES AS HISTAMINE-3 ANTAGONISTS
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The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.
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Page/Page column 14
(2009/04/24)
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- TRYCLIC NITROGEN CONTAINING COMPOUNDS AND THEIR USE AS ANTIBACTERIALS
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Tricyclic nitrogen containing compounds of formula (I) and their use as antibacterials.
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Page/Page column 76
(2008/06/13)
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- PYRROLO-QUINOXALINONE DERIVATIVES AS ANTIBACTERIALS
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Tricyclic nitrogen containing compounds of the following Formula (I) and their use as antibacterials.
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Page/Page column 55
(2008/06/13)
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