- Design, synthesis and evaluation of 3-amide-5-aryl benzoic acid derivatives as novel P2Y14R antagonists with potential high efficiency against acute gouty arthritis
-
P2Y14 nucleotide receptor plays important roles in series of physiological and pathologic events especially associated with immune and inflammation. Based on the 3-amide benzoic acid scaffold reported by our group previously, a series of 5-aryl-3-amide benzoic acid derivatives were designed as novel P2Y14 antagonists with improved pharmacokinetic properties. Among which compound 11m showed most potent P2Y14 antagonizing activity with an IC50 value of 2.18 nM, furnishing greatly improved water solubility and bioavailability compared with PPTN. In MSU-induced acute gouty arthritis model in mice, 11m exerted promising in vivo efficacy in alleviating mice paw swelling and inflammatory infiltration. Mechanistically, compound 11m notably blocked pyroptosis of macrophages through inhibiting NLRP3 inflammasome activation. This work may contribute to the identification of potential therapeutic agents to intervene in acute gouty arthritis.
- Lu, Ran,Wang, Yilin,Liu, Chunxiao,Zhang, Zhenguo,Li, Baiyang,Meng, Zibo,Jiang, Cheng,Hu, Qinghua
-
-
Read Online
- Light and chemically driven molecular machines showing a unidirectional four-state switching cycle
-
The imitation of macroscopic movements at the molecular level is a key step in the development of nanomachines. The challenge is the synthesis of molecules that are able to transform external stimuli into a direction-controlled mechanical movement. The more complex such motion sequences are, the more difficult is the construction of the corresponding nanomachine. Here, we present a system that demonstrates a unidirectional, four-state switching cycle that bears similar characteristics to the arm movements of a human breaststroke swimmer. Like the latter, the molecules have a torso and two arms. The arms consist of bipyridine units and can be folded and stretched by addition and removal of copper ions. The unidirectional rotation of the arms is achieved by light-induced switching of an azo unit.
- Haberhauer, Gebhard,Burkhart, Christoph,Woitschetzki, Sascha,W?lper, Christoph
-
-
Read Online
- MACROCYCLIC RIP2-KINASE INHIBITORS
-
The present invention relates to macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of RIP2-kinase, and/or mutants thereof, for use in the diagnosis, prevention and/or treatment of RIP2-kinase associated diseases. Moreover, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent.
- -
-
Page/Page column 76
(2021/08/06)
-
- Structure-Activity Relationship of Heterocyclic P2Y14Receptor Antagonists: Removal of the Zwitterionic Character with Piperidine Bioisosteres
-
A known zwitterionic, heterocyclic P2Y14R antagonist 3a was substituted with diverse groups on the central phenyl and terminal piperidine moieties, following a computational selection process. The most potent analogues contained an uncharged piperidine bioisostere, prescreened in silico, while an aza-scan (central phenyl ring) reduced P2Y14R affinity. Piperidine amide 11, 3-aminopropynyl 19, and 5-(hydroxymethyl)isoxazol-3-yl) 29 congeners in the triazole series maintained moderate receptor affinity. Adaption of 5-(hydroxymethyl)isoxazol-3-yl gave the most potent naphthalene-containing (32; MRS4654; IC50, 15 nM) and less active phenylamide-containing (33) scaffolds. Thus, a zwitterion was nonessential for receptor binding, and molecular docking and dynamics probed the hydroxymethylisoxazole interaction with extracellular loops. Also, amidomethyl ester prodrugs were explored to reversibly block the conserved carboxylate group to provide neutral analogues, which were cleavable by liver esterase, and in vivo efficacy demonstrated. We have, in stages, converted zwitterionic antagonists into neutral molecules designed to produce potent P2Y14R antagonists for in vivo application.
- Jung, Young-Hwan,Salmaso, Veronica,Wen, Zhiwei,Bennett, John M.,Phung, Ngan B.,Lieberman, David I.,Gopinatth, Varun,Randle, John C. R.,Chen, Zhoumou,Salvemini, Daniela,Karcz, Tadeusz P.,Cook, Donald N.,Jacobson, Kenneth A.
-
p. 5099 - 5122
(2021/05/05)
-
- Exploration of Alternative Scaffolds for P2Y14Receptor Antagonists Containing a Biaryl Core
-
Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y14 receptor (P2Y14R) antagonists were synthesized, and affinity was measured in P2Y14R-expressing Chinese hamster ovary cells by flow cytometry. Given this series' low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central m-benzoic acid core (25) provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2Y14R region is predicted by homology modeling as a deep, sterically limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic-substituted piperidine ring derivatives of naphthalene antagonist 1, e.g., quinuclidine 17 (MRS4608, IC50 ≈ 20 nM at hP2Y14R/mP2Y14R), or of triazole 2, preserved affinity. Potent antagonists 1, 7a, 17, and 23 (10 mg/kg) protected in an ovalbumin/Aspergillus mouse asthma model, and PEG conjugate 12 reduced chronic pain. Thus, we expanded P2Y14R antagonist structure-activity relationship, introducing diverse physical-chemical properties.
- Jung, Young-Hwan,Yu, Jinha,Wen, Zhiwei,Salmaso, Veronica,Karcz, Tadeusz P.,Phung, Ngan B.,Chen, Zhoumou,Duca, Sierra,Bennett, John M.,Dudas, Steven,Salvemini, Daniela,Gao, Zhan-Guo,Cook, Donald N.,Jacobson, Kenneth A.
-
p. 9563 - 9589
(2020/09/02)
-
- Novel sulfamoylbenzoates as antifungal agents against Malassezia furfur
-
Novel polyfunctional arenesulfonamides as potential fungicides were prepared in eight steps from 3-amino-5-bromobenzoic acid. Among them, methyl 3-bromo-2-nitro-5-(N-phenylsulfamoyl)benzoate exhibiting significant cytotoxic activity against Malassezia fur
- Trifonov, Lena,Chumin, Katerina,Gvirtz, Raanan,Afri, Michal,Korshin, Edward E.,Cohen, Guy,Gruzman, Arie
-
p. 709 - 711
(2021/01/12)
-
- PROTEIN KINASE INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
-
The invention relates to compounds of formula (I) which are inhibitors of MKK4 (mitogen-activated protein kinase kinase 4) and their use in promoting liver regeneration or reducing or preventing hepatocyte death. The compounds selectively inhibit protein kinase MKK4 over protein kinases JNK and MKK7. (I), wherein R x, R y , R z and R zz are selected from: a) R x and R y are F and R z and R zz are H; b) R x, R y and R zz are independently halogen and R z is H; c) R x R z and R zz are independently halogen and R y is H; and d) R x R y and R z are independently halogen and R zz is H
- -
-
Page/Page column 40; 41; 52; 53
(2020/02/14)
-
- HETEROCYCLIC P2Y14 RECEPTOR ANTAGONISTS
-
Disclosed are compounds of formulas (I)-(IX) for treating or preventing a disease or disorder responsive to antagonism of a P2Y14R receptor agonist in a mammal in need thereof, wherein R1-R8, X, Y, Z, X', Y', Z', and A are
- -
-
Paragraph 0203-0204
(2019/08/29)
-
- Design, synthesis and anti-inflammatory evaluation of 3-amide benzoic acid derivatives as novel P2Y14 receptor antagonists
-
The P2Y14 receptor (P2Y14R) plays a key role in the modulation of inflammatory process, but very few classes of antagonists have been reported. A series of 3-amide benzoic acid derivatives were identified as novel and potent P2Y
- Zhang, Zhenguo,Hao, Kun,Li, Hanwen,Lu, Ran,Liu, Chunxiao,Zhou, Mengze,Li, Baiyang,Meng, Zibo,Hu, Qinghua,Jiang, Cheng
-
-
- Structure-Guided Modification of Heterocyclic Antagonists of the P2Y14 Receptor
-
The P2Y14 receptor (P2Y14R) mediates inflammatory activity by activating neutrophil motility, but few classes of antagonists are known. We have explored the structure-activity relationship of a 3-(4-phenyl-1H-1,2,3-triazol-1-yl)-5-(aryl)benzoic acid antagonist scaffold, assisted by docking and molecular dynamics (MD) simulation at a P2Y14R homology model. A computational pipeline using the High Throughput MD Python environment guided the analogue design. Selection of candidates was based upon ligand-protein shape and complementarity and the persistence of ligand-protein interactions over time. Predictions of a favorable substitution of a 5-phenyl group with thiophene and an insertion of a three-methylene spacer between the 5-aromatic and alkyl amino moieties were largely consistent with empirical results. The substitution of a key carboxylate group on the core phenyl ring with tetrazole or truncation of the 5-aryl group reduced affinity. The most potent antagonists, using a fluorescent assay, were a primary 3-aminopropyl congener 20 (MRS4458) and phenyl p-carboxamide 30 (MRS4478).
- Yu, Jinha,Ciancetta, Antonella,Dudas, Steven,Duca, Sierra,Lottermoser, Justine,Jacobson, Kenneth A.
-
supporting information
p. 4860 - 4882
(2018/06/20)
-
- 3-acylamino benzoic acid derivatives as well as preparation method and medical application thereof
-
The invention belongs to the field of medicinal chemistry and relates to 3-acylamino benzoic acid derivatives, pharmaceutical composition containing the compounds, a preparation method of the derivatives and an application of the derivatives as a therapeutic agent in the aspect of medical treatment, in particular to a medical application of the derivatives as a P2Y14 receptor antagonist.
- -
-
Paragraph 0054-0056
(2019/01/16)
-
- A Light- and Electricity-Driven Molecular Pushing Motor
-
The synthesis and investigation of molecular artificial motors have been subject to massive developments in recent years. One challenge is to design machines driven by “clean” stimuli. Types of energies are considered as “clean” stimuli if their use leads to (almost) no side-products, no byproducts, no dilution, or any other disruptive effects. We present herein a pushing motor that is driven by light and electricity, both being considered as “clean” stimuli. The switching units of the motor are an azobenzene and a thianthrene. The former is triggered by light, whereas the latter changes its structure as a result of a redox process achieved by cyclic voltammetry. The four states of the molecular motor were identified by quantum chemical methods and UV/Vis spectroscopy. The switching cycles can be performed several times without significant changes in the signals.
- Burkhart, Christoph,Haberhauer, Gebhard
-
p. 1308 - 1317
(2017/03/23)
-
- TRIAZOLE DERIVATIVES AS P2Y14 RECEPTOR ANTAGONISTS
-
Described are compounds, which are antagonists of the P2Y14 receptor, for example, a compound of formula (I) in which ring A, R1,R2, R3, and n are as described herein. Also provided are dendron conjugates comprising the compounds, and methods of using the compounds, including a method of treating a disorder, such as inflammation, diabetes, insulin resistance, hyperglycemia, a lipid disorder, obesity, a condition associated with metabolic syndrome, and asthma, and a method of antagonizing P214 receptor activity in a cell.
- -
-
Paragraph 0109; 0110
(2017/04/11)
-
- EZH2 INHIBITORS AND USES THEREOF
-
The present disclosure provides compounds of any one of Formulae (I), (II), and (III). The compounds described herein are inhibitors of histone methyltransferases (e.g., enhancer of zeste homolog 1 (EZHl) and enhancer of zeste homolog 2 (EZH2)) and are useful in treating and/or preventing a broad range of diseases (e.g., proliferative diseases). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein.
- -
-
Paragraph 00342
(2017/11/15)
-
- Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y14 Receptor Antagonists
-
UDP and UDP-glucose activate the P2Y14 receptor (P2Y14R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y14R homology model based on P2Y12R structures. By reevaluating the binding of 3 to P2Y14R computationally, two alternatives, i.e., alkynyl and triazolyl derivatives, were identified. Improved synthesis of fluorescent antagonist 4 enabled affinity quantification (IC50s, nM) using flow cytometry of P2Y14R-expressing CHO cells. p-F3C-phenyl-triazole 65 (32) was more potent than a corresponding alkyne 11. Thus, additional triazolyl derivatives were prepared, as guided by docking simulations, with nonpolar aryl substituents favored. Although triazoles were less potent than 3 (6), simpler synthesis facilitated further structural optimization. Additionally, relative P2Y14R affinities agreed with predicted binding of alkynyl and triazole analogues. These triazoles, designed through a structure-based approach, can be assessed in disease models.
- Junker, Anna,Balasubramanian, Ramachandran,Ciancetta, Antonella,Uliassi, Elisa,Kiselev, Evgeny,Martiriggiano, Chiara,Trujillo, Kevin,Mtchedlidze, Giorgi,Birdwell, Leah,Brown, Kyle A.,Harden, T. Kendall,Jacobson, Kenneth A.
-
supporting information
p. 6149 - 6168
(2016/07/26)
-
- The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat
-
Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation of histone methylation can lead to oncogenic transformation. Enhancer of Zeste homologue 2 (EZH2) methylates histone 3 at lysine 27 (H3K27) and abnormal methylation of this site is found in many cancers. Tazemetostat, an EHZ2 inhibitor in clinical development, has shown activity in both preclinical models of cancer as well as in patients with lymphoma or INI1-deficient solid tumors. Herein we report the structure-activity relationships from identification of an initial hit in a high-throughput screen through selection of tazemetostat for clinical development. The importance of several methyl groups to the potency of the inhibitors is highlighted as well as the importance of balancing pharmacokinetic properties with potency.
- Kuntz, Kevin W.,Campbell, John E.,Keilhack, Heike,Pollock, Roy M.,Knutson, Sarah K.,Porter-Scott, Margaret,Richon, Victoria M.,Sneeringer, Chris J.,Wigle, Tim J.,Allain, Christina J.,Majer, Christina R.,Moyer, Mikel P.,Copeland, Robert A.,Chesworth, Richard
-
supporting information
p. 1556 - 1564
(2016/03/05)
-
- Conformational and Chiral Properties of Cyclic-tri(N-methyl-meta-benzamide) Bearing Amidino Groups
-
Cyclic triamides 4 bearing amidino groups at the meta position of the phenyl rings were synthesized, and their conformational properties in the crystal and in solution were examined. Compound 4a exists as a capsule-type dimer of the enantiomers with a bowl-shaped syn conformation in the crystal state. Compound 4 exists mainly in the syn form in solution, and chiral induction was observed upon addition of a chiral acid to a solution of 4a. Chirality 27:487-491, 2015.
- Nishiyama, Shizuka,Urushibara, Ko,Masu, Hyuma,Azumaya, Isao,Kagechika, Hiroyuki,Tanatani, Aya
-
supporting information
p. 487 - 491
(2015/08/03)
-
- Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections
-
Targeting PqsD is a promising novel approach to disrupt bacterial cell-to-cell-communication in Pseudomonas aeruginosa. In search of selective PqsD inhibitors, two series of benzamidobenzoic acids - one published as RNAP inhibitors and the other as PqsD inhibitors - were investigated for inhibitory activity toward the respective other enzyme. Additionally, novel derivatives were synthesized and biologically evaluated. By this means, the structural features needed for benzamidobenzoic acids to be potent and, most notably, selective PqsD inhibitors were identified. The most interesting compound of this study was the 3-Cl substituted compound 5 which strongly inhibits PqsD (IC 50 6.2 μM) while exhibiting no inhibition of RNAP.
- Hinsberger, Stefan,De Jong, Johannes C.,Groh, Matthias,Haupenthal, J?rg,Hartmann, Rolf W.
-
p. 343 - 351
(2014/03/21)
-
- NOVEL CHARTREUSIN ANALOGUES
-
The present invention relates to novel Chartreusin analogues of formula (I), pharmaceutical compositions comprising the same and to their use for the treatment of cancer and other diseases.
- -
-
Page/Page column 13; 39; 40
(2014/02/16)
-
- Synthetic remodeling of the chartreusin pathway to tune antiproliferative and antibacterial activities
-
Natural products of the benzonaphthopyranone class, such as chartreusin, elsamicin A, gilvocarcin, and polycarcin, represent potent leads for urgently needed anticancer therapeutics and antibiotics. Since synthetic protocols for altering their architectur
- Ueberschaar, Nico,Xu, Zhongli,Scherlach, Kirstin,Metsae-Ketelae, Mikko,Bretschneider, Tom,Dahse, Hans-Martin,Goerls, Helmar,Hertweck, Christian
-
supporting information
p. 17408 - 17416
(2014/01/06)
-
- New multifunctional phosphonic acid for metal phosphonate synthesis
-
A new heterotopic phosphonic acid, 3-amino-5-(dihydroxyphosphoryl)benzoic acid (1) has been synthesized and obtained in the crystalline form. Second multifunctional phosphonic acid-namely 3-(dihydroxyphosphoryl)-5-nitrobenzoic acid (2) has also been obtai
- Garczarek, Piotr,Janczak, Jan,Zoń, Jerzy
-
p. 505 - 509
(2013/04/10)
-
- Preparation of molecular cage by coordination of m-Calix[3]amide bearing pyridine with palladium complex
-
m-Calix[3]amide having pyridine on the benzene ring (PyC3A) was synthesized by the cyclization of methyl 3-nonylamino-5-(pyridin-4-yl)benzoate using lithium 1,1,1,3,3,3-hexamethyldisilazide (LiHMDS). The molecular cage 3Pd· 2PyC3A was prepared from a 2:3 mixture of PyC3A and [Pd(dppp)(OTf)2] in CDCl3/CD3OD (5/1 in volume). On the other hand, in CDCl3, the formation of a polymeric mixture was confirmed.
- Yamakado, Ryohei,Sugimoto, Shinri,Matsuoka, Shin-Ichi,Suzuki, Masato,Funahashi, Yasuhiro,Takagi, Koji
-
supporting information; scheme or table
p. 249 - 251
(2012/06/01)
-
- Synthesis and molecular modeling study of new trimeric quinoline derivatives
-
Di- and trimeric quinoline derivatives have been recently described as potential modulators of Bcl-2 family protein interactions. However, only a few trimeric compounds have been described so far and an enlargement of the number of analogs of this class is needed to expand the structure-activity relationship study. Therefore, the synthesis of six new trimeric quinoline derivatives is reported. Moreover molecular modeling experiments were performed to study the conformational arrangement of compound 36 in Bak binding site of Bcl-x L, showing that these compounds could be potential ligands for Bcl-xL.
- Saugues, Emmanuelle,Nauton, Lionel,Thery, Vincent,Anizon, Fabrice,Moreau, Pascale
-
scheme or table
p. 143 - 150
(2011/11/01)
-
- Self-assembly of oligothiophene chromophores by m -calix[3]amide scaffold
-
m-Calix[3]amides carrying the bithiophene chromophore (BTC3A) and terthiophene chromophore (TTC3A) were synthesized by the cyclic trimerization of m-aminobenzoic acid esters for the purpose of the control and understanding of the self-assembly of oligothiophene chromophores. Polymers and model compounds were also prepared for comparison. From the 1H NMR experiments, cyclic trimer BTC3A showed the syn/anti equilibrium in solution, and the syn/anti conformer ratio (76/24 in CDCl3) was influenced by the solvent character. Namely, the population of the syn conformer was lowest (70%) in THF-d8 and was highest (86%) in CDCl3/CD3OD (1/1 in volume). On the other hand, the population of the syn conformer of cyclic trimer TTC3A was high (84%) even in CDCl3. In a CHCl 3 solution of cyclic trimer BTC3A, the absorption maximum (342 nm) blue-shifted and the emission maximum (448 nm) red-shifted compared with those of polymer BTPA and model compound BTM. The solvent character also had an impact on the optical properties of cyclic trimer BTC3A. The red-shifted emission maximum (481 nm) of cyclic trimer BTC3A in CH3OH indicated the interaction between three bithiophene chromophores. The emission maxima of cyclic trimer TTC3A (486 nm) demonstrated a small red-shift from model compound TTM (477 nm), and no solvent dependency was observed, unlike cyclic trimer BTC3A.
- Takagi, Koji,Sugimoto, Shinri,Yamakado, Ryohei,Nobuke, Katsuya
-
experimental part
p. 2471 - 2478
(2011/06/24)
-
- Synthesis and biological activities of new di-and trimeric quinoline derivatives
-
The synthesis of non-peptidic helix mimetics based on a trimeric quinoline scaffold is described. The ability of these new compounds, as well as their synthetic dimeric intermediates, to bind to various members of the Bcl-2 protein anti-apoptotic group is also evaluated. The most interesting derivative of this new series (compound A) inhibited Bcl-xL/Bak, Bcl-xL/Bax and Bcl-xL/Bid interactions with IC50 values around 25 μM.
- Broch, Sidonie,Héènon, Hélne,Debaud, Anne-Laure,Fogeron, Marie-Laure,Bonnefoy-Bérard, Nathalie,Anizon, Fabrice,Moreau, Pascale
-
experimental part
p. 7132 - 7143
(2010/11/02)
-
- Cyclic-tri(N-methyl-meta-benzamide)s: Substituent effects on the bowl-shaped conformation in the crystal and solution states
-
Cyclic trimers of 3-(N-alkylamino)benzoic acid (calix[3]amides) with various substituents at the meta position of the phenyl rings were synthesized and the effects of the substituents on the crystal structures and energy profiles in solution were examined. The calixamides existed in a syn conformation in the crystal state, and this was also the major conformation in solution, especially in polar solvents. The energy barrier between syn and anti conformers in the solution was not significantly affected by substituents (12.7-14.0 kcal/mol). The effect of the substituent on the temperature dependence of the syn/anti ratio are discussed.
- Kakuta, Hiroki,Azumaya, Isao,Masu, Hyuma,Matsumura, Mio,Yamaguchi, Kentaro,Kagechika, Hiroyuki,Tanatani, Aya
-
experimental part
p. 8254 - 8260
(2010/11/02)
-
- Synthesis and evaluation of 3-(dihydroxyboryl)benzoic acids as D,D-carboxypeptidase R39 inhibitors
-
Penicillin binding proteins (PBPs) catalyze steps in the biosynthesis of bacterial cell walls and are the targets for the β-lactam antibiotics. Non-β-lactam based antibiotics that target PBPs are of interest because bacteria have evolved resistance to the
- Inglis, Steven R.,Zervosen, Astrid,Woon, Esther C. Y.,Gerards, Thomas,Teller, Nathalie,Fischer, Delphine S.,Luxen, André,Schofield, Christopher J.
-
supporting information; experimental part
p. 6097 - 6106
(2010/03/24)
-
- HYDROXYETHYLAMINE DERIVATIVES FOR THE TREATMENT OF ALZHEIMER'S DISEASE
-
The present invention relates to novel hydroxyethylamine compounds of formula (I): (I) having Asp2 (-secretase, BACE1 or Memapsin) inhibitory activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases characterised by elevated-amyloid levels or-amyloid deposits, particularly Alzheimer's disease.
- -
-
-
- Shape-persistent cyclyne-type azamacrocycles: Synthesis, unusual light-emitting characteristics, and specific recognition of the Sb(V) ion
-
Simple members of arene-azaarenecyclynes as a novel family of geometrically-controlled and shape-persistent azamacrocycles have been synthesized. Noteworthy is the specific recognition function for Sb(V). The synthesized azamacrocycles, in particular the
- Kobayashi, Shigeya,Yamaguchi, Yoshihiro,Wakamiya, Tateaki,Matsubara, Yoshio,Sugimoto, Kunihisa,Yoshida, Zen-Ichi
-
p. 1469 - 1472
(2007/10/03)
-