- Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists
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The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan-1-yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand-based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two-electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl-cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2-chloro-N-[1-(3-(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide (56) exhibiting the best potency with an IC50 value of 0.39 μΜ.
- Durner, Anna,Koufaki, Maria,Kritsi, Eftichia,Nicke, Annette,Papakostas, Alexios,T. Pournara, Dimitra,Zoumpoulakis, Panagiotis
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supporting information
p. 2530 - 2543
(2020/10/19)
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- CARBORANE-BASED HISTONE DEACETYLASE (HDAC) INHIBITORS
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The present disclosure provides compounds and compositions capable of treating cancer, a disease of the central nervous system, and an inflammatory autoimmune disease, and methods of use thereof.
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Page/Page column 53
(2020/07/04)
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- Continuous-Flow Hydrogenation and Reductive Deuteration of Nitriles: a Simple Access to α,α-Dideutero Amines
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A simple and efficient continuous flow methodology has been developed for hydrogenation and reductive deuteration of nitriles to yield primary amines and also valuable α,α-dideutero analogues. Raney nickel proved to be a useful catalyst for the transformation of a wide range of nitriles under reasonably mild conditions with excellent deuterium incorporation (>90 %) and quantitative conversion. Among known model compounds, three new deuterated primary amines were prepared. The large-scale synthesis of deuterated tryptamine was also carried out to deliver 1.1 g product under flow conditions.
- Mészáros, Rebeka,Peng, Bai-Jing,?tv?s, Sándor B.,Yang, Shyh-Chyun,Fül?p, Ferenc
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p. 1508 - 1511
(2019/11/03)
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- Systematic structure-activity relationship (SAR) exploration of diarylmethane backbone and discovery of a highly potent novel uric acid transporter 1 (URAT1) inhibitor
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In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a-1x and 1ha-1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200-and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 μM against human URAT1 for 1h vs. 7.18 μM and 0.28 μM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.
- Cai, Wenqing,Wu, Jingwei,Liu, Wei,Xie, Yafei,Liu, Yuqiang,Zhang, Shuo,Xu, Weiren,Tang, Lida,Wang, Jianwu,Zhao, Guilong
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- The role of polycyclic frameworks in modulating P2X7 receptor function
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Herein we describe our recent attempts to target the P2X7 receptor for potential treatment of neurological disorders. This work focusses on different polycycles including carborane, adamantane or cubane, joined by either a cyanoguanidine or an amide linker to phenyl or isoquinoline moieties. We have demonstrated the superiority of the adamantyl moiety over other polycycles in terms of synthetic accessibility and biological (cellular) activity. We have also shown that an amide or cyanoguanidine linker can greatly alter the biological activity of compounds. This SAR study provides important insights into the types of functionality required to target the P2X7 receptor.
- Callis, Timothy B.,Reekie, Tristan A.,O'Brien-Brown, James,Wong, Erick C.N.,Werry, Eryn L.,Elias, Nabiha,Jorgensen, William T.,Tsanaktsidis, John,Rendina, Louis M.,Kassiou, Michael
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p. 1207 - 1219
(2017/11/24)
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- Cobalt-based nanoparticles prepared from MOF-carbon templates as efficient hydrogenation catalysts
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The development of efficient and selective nanostructured catalysts for industrially relevant hydrogenation reactions continues to be an actual goal of chemical research. In particular, the hydrogenation of nitriles and nitroarenes is of importance for the production of primary amines, which constitute essential feedstocks and key intermediates for advanced chemicals, life science molecules and materials. Herein, we report the preparation of graphene shell encapsulated Co3O4- and Co-nanoparticles supported on carbon by the template synthesis of cobalt-terephthalic acid MOF on carbon and subsequent pyrolysis. The resulting nanoparticles create stable and reusable catalysts for selective hydrogenation of functionalized and structurally diverse aromatic, heterocyclic and aliphatic nitriles, and as well as nitro compounds to primary amines (>65 examples). The synthetic and practical utility of this novel non-noble metal-based hydrogenation protocol is demonstrated by upscaling several reactions to multigram-scale and recycling of the catalyst.
- Murugesan, Kathiravan,Senthamarai, Thirusangumurugan,Sohail, Manzar,Alshammari, Ahmad S.,Pohl, Marga-Martina,Beller, Matthias,Jagadeesh, Rajenahally V.
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p. 8553 - 8560
(2018/11/30)
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- Reduction of selenoamides to amines using SmI2-H2O
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Selenoamides are selectively reduced to amines by SmI2 with H2O. The process is general for primary, secondary, and tertiary aryl and alkyl selenoamide substrates and selectively delivers amine products. The reduction proceeds under mild conditions using SmI2 activated by straightforward addition of H2O, and does not require an additional Lewis base additive.
- Thurow, Samuel,Lenardo, Eder J.,Just-Baringo, Xavier,Procter, David J.
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supporting information
p. 50 - 53
(2017/11/28)
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- NOVEL ADAMANTANE AND MEMANTINE DERIVATIVES AS PERIPHERAL NMDA RECEPTOR ANTAGONISTS
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The present invention relates to cationic compounds of formula (I) for use as peripheral NMDA receptor antagonists.
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Page/Page column 18
(2017/02/24)
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- COMPOUNDS AND METHODS FOR TREATMENT OF CANCER BY INHIBITING ATG4B AND BLOCKING AUTOPHAGY
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ATG4B inhibitor compounds, compositions that include the compounds, and methods for using the compounds and compositions in the treatment of cancer by inhibiting ATG4B and/or blocking autophagy.
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Page/Page column 33; 34; 39; 40
(2017/03/14)
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- Selective Hydrogenation of Nitriles to Primary Amines by using a Cobalt Phosphine Catalyst
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A general procedure for the catalytic hydrogenation of nitriles to primary amines by using a non-noble metal-based system is presented. Co(acac)3 in combination with tris[2-(dicyclohexylphosphino)ethyl]phosphine efficiently catalyzes the selective hydrogenation of a wide range of (hetero)aromatic and aliphatic nitriles to give the corresponding amines.
- Adam, Rosa,Bheeter, Charles Beromeo,Cabrero-Antonino, Jose R.,Junge, Kathrin,Jackstell, Ralf,Beller, Matthias
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p. 842 - 846
(2017/03/17)
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- Hydride Reduction by a Sodium Hydride-Iodide Composite
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Sodium hydride (NaH) is widely used as a Br?nsted base in chemical synthesis and reacts with various Br?nsted acids, whereas it rarely behaves as a reducing reagent through delivery of the hydride to polar π electrophiles. This study presents a series of reduction reactions of nitriles, amides, and imines as enabled by NaH in the presence of LiI or NaI. This remarkably simple protocol endows NaH with unprecedented and unique hydride-donor chemical reactivity.
- Too, Pei Chui,Chan, Guo Hao,Tnay, Ya Lin,Hirao, Hajime,Chiba, Shunsuke
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supporting information
p. 3719 - 3723
(2016/03/26)
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- Metal-Free Oxidation of Primary Amines to Nitriles through Coupled Catalytic Cycles
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Synergism among several intertwined catalytic cycles allows for selective, room temperature oxidation of primary amines to the corresponding nitriles in 85-98 % isolated yield. This metal-free, scalable, operationally simple method employs a catalytic quantity of 4-acetamido-TEMPO (ACT; TEMPO=2,2,6,6-tetramethylpiperidine N-oxide) radical and the inexpensive, environmentally benign triple salt oxone as the terminal oxidant under mild conditions. Simple filtration of the reaction mixture through silica gel affords pure nitrile products.
- Lambert, Kyle M.,Bobbitt, James M.,Eldirany, Sherif A.,Kissane, Liam E.,Sheridan, Rose K.,Stempel, Zachary D.,Sternberg, Francis H.,Bailey, William F.
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p. 5156 - 5159
(2016/04/09)
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- Selective catalytic hydrogenation of nitriles to primary amines using iron pincer complexes
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The selective catalytic hydrogenation of nitriles to primary amines with the well-defined Fe(PNPCy) pincer complex 2 is reported. This iron pincer catalyst shows superior catalytic activity and selectivity in the reduction of various nitriles including industrially relevant adipodinitrile in high yields under relatively mild conditions.
- Lange,Elangovan,Cordes,Spannenberg,Jiao,Junge,Bachmann,Scalone,Topf,Junge,Beller
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p. 4768 - 4772
(2016/07/11)
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- A Mild and Base-Free Protocol for the Ruthenium-Catalyzed Hydrogenation of Aliphatic and Aromatic Nitriles with Tridentate Phosphine Ligands
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A novel protocol for the general hydrogenation of nitriles in the absence of basic additives is described. The system is based on the combination of [Ru(cod)(methylallyl)2] (cod=cyclooctadiene) and L2. A variety of aromatic and aliphatic nitriles is hydrogenated under mild conditions (50 °C and 15 bar H2) with this system. Kinetic studies revealed higher activity in the case of aromatic nitriles compared with aliphatic ones.
- Adam, Rosa,Bheeter, Charles Beromeo,Jackstell, Ralf,Beller, Matthias
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p. 1329 - 1334
(2016/04/20)
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- C H Bond Arylation of Diamondoids Catalyzed by Palladium(II) Acetate
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We have developed an effective approach to 1,2-disubstituted diamondoids by palladium(II) acetate catalyzed functionalization of C H bond. Selective mono-arylation of the adamantane framework was achieved using picolylamide as a directing group in yields up to 87 %. Kinetic studies in combination with deuterium labeling experiments, competitive experiments and mass spectrometry contribute to the mechanistic understanding of the arylation process of alkanes with number of C H bonds neighboring the directing group. Triflic anhydride promoted cyclization of the directing group generates imidazo[1,5-a]pyridine derivatives. Acid-mediated removal of the directing group provides access to 2-aryl diamondoid carboxylic acids, which are common precursors for the synthesis of various bioactive compounds (drug candidates). (Figure presented.) .
- Larrosa, Marta,Heiles, Sven,Becker, Jonathan,Spengler, Bernhard,Hrdina, Radim
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supporting information
p. 2163 - 2171
(2016/07/16)
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- Hydrogenation of Aliphatic and Aromatic Nitriles Using a Defined Ruthenium PNP Pincer Catalyst
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Selective catalytic reductions of nitriles are presented using the commercially available Ru-Macho-BH complex. A variety of aliphatic, aromatic and (hetero)cyclic nitriles including industrially important adipodinitrile are hydrogenated to the corresponding primary amines. Modelling suggests the reaction follows an outer sphere hydrogenation mechanism. An efficient and selective catalytic reduction of nitriles is presented using the commercially available Ru-Macho-BH complex. A variety of aliphatic, aromatic and (hetero)cyclic nitriles including the industrially important adipodinitrile are hydrogenated to the corresponding primary amines. The reaction follows an outer-sphere mechanism.
- Neumann, Jacob,Bornschein, Christoph,Jiao, Haijun,Junge, Kathrin,Beller, Matthias
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supporting information
p. 5944 - 5948
(2015/09/22)
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- Structure-activity relationships of N-substituted 4-(trifluoromethoxy) benzamidines with affinity for GluN2B-containing NMDA receptors
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GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptomatic treatment of multiple CNS pathologies. A series of N-benzyl substituted benzamidines were synthesised and the benzyl ring was further replaced with various polycyclic moieties. Compounds were evaluated for activity at GluN2B containing NMDA receptors where analogues 9, 12, 16 and 18 were the most potent of the series, replacement of the benzyl ring with polycycles resulted in a complete loss of activity.
- Beinat, Corinne,Banister, Samuel D.,Hoban, Jane,Tsanaktsidis, John,Metaxas, Athanasios,Windhorst, Albert D.,Kassiou, Michael
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p. 828 - 830
(2014/02/14)
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- The first cns-active carborane: A novel p2x7 receptor antagonist with antidepressant activity
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Relative to other polycyclic frameworks (1-3), a carborane cage (4 and Cs·5) exerts a significant biological effect as an inhibitor of the purinergic P2X7 receptor (P2X7R) which allows one to target depression in vivo and thus demonstrate, for the first time, that a carborane has the capacity to modify CNS activity.
- Wilkinson, Shane M.,Gunosewoyo, Hendra,Barron, Melissa L.,Boucher, Aurelie,McDonnell, Michelle,Turner, Peter,Morrison, Daniel E.,Bennett, Maxwell R.,McGregor, Iain S.,Rendina, Louis M.,Kassiou, Michael
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p. 335 - 339
(2014/06/09)
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- Electron transfer reduction of nitriles using SmI2-Et 3N-H2O: Synthetic utility and mechanism
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The first general reduction of nitriles to primary amines under single electron transfer conditions is demonstrated using SmI2 (Kagan's reagent) activated with Lewis bases. The reaction features excellent functional group tolerance and represents an attractive alternative to the use of pyrophoric alkali metal hydrides. Notably, the electron transfer from Sm(II) to CN functional groups generates imidoyl-type radicals from bench stable nitrile precursors.
- Szostak, Michal,Sautier, Brice,Spain, Malcolm,Procter, David J.
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supporting information
p. 1092 - 1095
(2014/03/21)
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- Ruthenium/imidazolylphosphine catalysis: Hydrogenation of aliphatic and aromatic nitriles to form amines
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A convenient and efficient catalyst system for the hydrogenation of aliphatic nitriles towards the corresponding primary amines in high to excellent yields is presented. In addition, aromatic nitriles are reduced smoothly, too. The use of low catalyst loadings and molecular hydrogen make this protocol an attractive methodology. It's not complicated: A general and easy homogeneous catalyst system based on [Ru(cod)(methylallyl)2] and a cyclohexyl-substituted imidazolylphosphine ligand for selective hydrogenation of aliphatic nitriles is presented. In addition, by using an isopropyl-substituted imidazolylphosphine ligand, selected aromatic nitriles were reduced with excellent yields towards the primary amine. Furthermore, two new crystal structures give an insight of possible pre-catalysts.
- Werkmeister, Svenja,Junge, Kathrin,Wendt, Bianca,Spannenberg, Anke,Jiao, Haijun,Bornschein, Christoph,Beller, Matthias
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supporting information
p. 4227 - 4231
(2014/05/06)
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- Selective ruthenium-catalyzed transfer hydrogenations of nitriles to amines with 2-butanol
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Transfer your hydrogen: Fast and general transfer hydrogenation of nitriles to form primary amines is possible with a homogeneous Ru/1,4- bis(diphenylphosphino)butane (DPPB) catalyst (see scheme). The use of 2-butanol as the hydrogen-transfer reagent is essential for the selective reduction of aromatic, heteroaromatic, and aliphatic nitriles with this system. Copyright
- Werkmeister, Svenja,Bornschein, Christoph,Junge, Kathrin,Beller, Matthias
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supporting information
p. 4437 - 4440
(2013/04/23)
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- Two iron catalysts are better than one: A general and convenient reduction of aromatic and aliphatic primary amides
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It takes two: For the reduction of amides to amines iron catalysts were developed. A combination of two different iron catalysts made possible the challenging reduction of primary amides (see picture). Copyright
- Das, Shoubhik,Wendt, Bianca,Moeller, Konstanze,Junge, Kathrin,Beller, Matthias
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supporting information; experimental part
p. 1662 - 1666
(2012/05/05)
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- Synthesis and anti-HIV studies of 2- and 3-adamantyl-substituted thiazolidin-4-ones
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A series of novel thiazolidin-4-ones bearing a lipophilic adamantyl substituent at position 2 or 3 were synthesized. A majority of them showed a modest anti-HIV-1 activity, whereas 2-adamantan-1-yl-3-(4,6-dimethylpyrimidin-2-yl)-thiazolidin-4-one (8) was endowed with a remarkable antiviral potency (EC50 = 0.67 μM). The new series of compounds (22-29) with an adamantyl moiety at the 3-position of the thiazolidinone ring showed good to modest anti-HIV-1 activity (EC50 = 1.0-11 μM) but also pronounced cytostatic activity. For example 24, 26 and 29 showed an EC50 of 1.0-2.0 μM, while the 50% effective concentrations for 23 and 28 were 7.8 and 11.0 μM, respectively. X-ray studies and quantum chemical calculations revealed that the anti-HIV activity of the compounds strongly depends on their dipole moments and conformation of the thiazolidinones.
- Balzarini, Jan,Orzeszko-Krzesinska, Barbara,Maurin, Jan K.,Orzeszko, Andrzej
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experimental part
p. 303 - 311
(2009/04/10)
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- CYCLIC UREA AND CARBAMATE INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE 1
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This invention relates to novel compounds of the Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11 beta-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of Cortisol in a cell or the inhibition of the conversion of cortisone to Cortisol in a cell.
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- POLYCYCLIC MOLECULAR COMPOUNDS
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This invention relates to compounds of Formula (I), wherein A is a carboaromatic or heteroaromatic ring having one or more substituents; R6 Formula (A) is optionally substituted with one or more substituents; and n is 0, 1 or an integer greater than 1 and when n is 1 or greater the bond or bonds between the carbon atoms may be saturated or unsaturated, which bind the P2X7 receptor with high affinity. This invention also relates to methods for the diagnosis, treatment or monitoring of disorders in which the P2X7 receptor is implicated, in particular the diagnosis, treatment or monitoring of (the progression of) neuroinflammatory and neurodegenerative disorders in a subject.
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Page/Page column 57; 61
(2008/12/06)
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- Cubyl amides: Novel P2X7 receptor antagonists
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Polycyclic amides 2 and 5-9 were successfully synthesised and their lipophilicity profiles were evaluated using reverse-phase HPLC. All synthesised compounds possessed P2X7R antagonistic properties when tested on rat spinal cord microglia cells. Extensive screening for binding to other neuroreceptor subtypes demonstrated their P2X7 selectivity.
- Gunosewoyo, Hendra,Guo, Jun Liu,Bennett, Maxwell R.,Coster, Mark J.,Kassiou, Michael
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supporting information; experimental part
p. 3720 - 3723
(2009/04/06)
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- NEW ADAMANTANE DERIVATIVES AS DIPEPTIDYL, PEPTIDASE IV INHIBITORS, PROCESSES FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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The present invention relates to dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula (A): wherein R1, R2, Y, and n are as defined herein, pharmaceutical compositions containing the same, processes for their preparation, and methods for treating disorders mediated by DPP-IV inhibition, such as diabetes, especially Type II diabetes, with them.
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Page/Page column 28
(2008/06/13)
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- NMDA receptor antagonists and their use in inhibiting abnormal hyperphosphorylation of microtubule associated protein tau
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Aminocyclohexane and aminoalkylcyclohexane compounds, which are systemic-ally-active as NMDA receptor antagonists, are effective in inhibiting abnormal hyperphosphorylation of microtubule associated protein tau, method of treating disorders resulting from or associated with abnormal hyperphosphorylation of microtubule associated protein tau, and pharmaceutical compositions comprising the same.
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- An artificial receptor for the intermolecular and enantioselective formation of peptide sheets
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Peptide strands coupled at the C terminus to bis[p(aminomethyl)phenyl] ether allow in CHCl3 solution association of lipophilic N-protected peptides with hydrogen bonds in the mode of antiparallel β-sheets; the enantioselectivity observed with a phenylalanine derivative is characterized by a binding constant ratio of around 15.
- Eblinger, Frank,Schneider, Hans-Joerg
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p. 2297 - 2298
(2007/10/03)
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- ADAMANTYL-CONTAINING THIOESTERS I. SYNTHESIS AND CHEMICAL TRANSFORMATIONS OF O-METHYL ADAMANTANE-1-CARBOTHIOATE
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O-Methyl adamantane-1-carbothioate was obtained for the first time by the reaction of methyl adamantane-1-carboxylate with phosphorus pentasulfide in dimethoxyethane or dioxane.Its reactions with hydroxylamine and O-methylhydroxylamine led to the preferential formation of 1-adamantyl cyanide and 1-adamantyl isothiocyanate respectively.The products from the reaction of the thioester with piperidine were the O-ester and piperidinium salt of adamantane-2-carbothioic O-acid, the formation of which was accompanied by N-alkylation of the amine.The reaction of the thioester and diazomethane gave adamantyl-containing thiadiazoles and thiadiazolines.
- Klimko, Yu. E.,Isaev, S. D.,Yurchenko, A. G.
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p. 1776 - 1783
(2007/10/03)
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- Adamantane derivatives in the prevention and treatment of cerebral ischemia
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A method for the prevention and treatment of cerebral ischemia using an adamantane derivative of the formula STR1 wherein R1 and R2 are identical or different, representing hydrogen or a straight or branched alkyl group of 1 to 6 C atoms or, in conjunction with N, a heterocyclic group with 5 or 6 ring C atoms; wherein R3 and R4 are identical or different, being selected from hydrogen, a straight or branched alkyl group of 1 to 6 C atoms, a cycloalkyl group with 5 or 6 C atoms, and phenyl; wherein R5 is hydrogen or a straight or branched C1 -C6 alkyl group, or a pharmaceutically-acceptable salt thereof, is disclosed.
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- Relative Reactivity of Bridgehead Adamantyl and Homoadamantyl Substrates from Solvolyses with Heptafluorobutyrate as a Highly Reactive Carboxylate Leaving Group. Absence of SN2 Character of Solvolysis of tert-Butyl Derivatives
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Heptafluorobutyrates, conveniently prepared from alcohols, possess a reactivity similar to that of halides in solvolysis reactions.A product and isotope distribution study for the reaction of 1-adamantyl heptafluorobutyrate (1a) in 80:20 ethanol-H2(18)O demonstrated exclusive alkyl-oxygen cleavage.The reactivities of 1a, 1-(2a), and 3-homoadamantyl heptafluorobutyrate (3a) increase with the flexibility of the hydrocarbon skeleton.The rate constants are linearly correlated with the strain increase upon ionization.No acceleration attributable to nucleophilic solvent assistance was evidenced for the tert-butyl ester, 4a.A literature proposal for such assistance in solvolyses of 4 is examined.The existing data are explained better by an SN1 process with electrophilic assistance of the leaving group in the solvents that can form very strong hydrogen bonds.
- Farcasiu, Dan,Jaehme, Joachim,Ruechardt, Christoph
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p. 5717 - 5722
(2007/10/02)
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