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https://www.readbyqxmd.com/read/28807572/identification-of-highly-selective-and-potent-orexin-receptor-1-antagonists-derived-from-a-dual-orexin-receptor-1-2-antagonist-based-on-the-structural-framework-of-pyrazoylethylbenzamide
#1
Aya Futamura, Dai Nozawa, Yuko Araki, Yunoshin Tamura, Seiken Tokura, Hiroshi Kawamoto, Yuichi Tokumaru, Sora Kakihara, Takeshi Aoki, Norikazu Ohtake
The design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead (1) by installing a (S)-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N-ethyl-5-fluoro-N-{(2S)-1-[5-(4-fluorophenyl)-2H-tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide (24), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC50 of 2...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28803210/investigation-of-ph-and-substituent-effects-on-the-distribution-ratio-of-novel-steroidal-ring-d-and-a-fused-arylpyrazole-regioisomers-and-evaluation-of-their-cell-growth-inhibitory-effects-in-vitro
#2
Ádám Baji, Ferenc Kovács, Gergő Mótyán, Gyula Schneider, János Wölfling, Izabella Sinka, István Zupkó, Imre Ocsovszki, Éva Frank
Novel androstanopyrazoles have been efficiently synthesized from steroidal β-ketoaldehydes with different arylhydrazine hydrochlorides both under acidic and basic conditions. Knorr-type transformations of 16-hydroxymethylene-dehydroepiandrosterone containing its 1,3-dicarbonyl moiety on ring D, proved to be regioselective in pyridine at room temperature, while mixtures of regioisomers were obtained in acidic EtOH under reflux. Contrarily, the cyclocondensation reactions of 2-hydroxymethylene-dihydrotestosterone bearing its reactive functionalities on ring A, led to a mixture of pyrazole regioisomers in varying ratio depending on the applied medium...
August 9, 2017: Steroids
https://www.readbyqxmd.com/read/28800456/synthesis-and-anticancer-properties-of-ruthenium-ii-complexes-as-potent-apoptosis-inducers-through-mitochondrial-disruption
#3
Dan Wan, Bing Tang, Yang-Jie Wang, Bo-Hong Guo, Hui Yin, Qiao-Yan Yi, Yun-Jun Liu
A new ligand MHPIP (MHPIP = 2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its three ruthenium (II) complexes [Ru(N-N)2(MHPIP)](ClO4)2 (N-N = phen: 1,10-phenanthroline 1; dmp = 2,9-dimethyl-1,10-phenanthroline 2; ttbpy = 4,4'-ditertiarybutyl-2,2'-bipyridine 3) were synthesized and characterized. The cytotoxic activity in vitro was studied by MTT method. The complexes 1-3 show moderate cytotoxic effects on the cell growth in HepG2 cells with an IC50 value of 25.5 ± 3.5, 35...
July 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28800377/antidote-to-cannabinoid-intoxication-inverse-cannabinoid-receptor-one-cb1-agonism-by-n-piperidin-1-yl-5-4-iodophenyl-1-2-4-dichlorophenyl-4-methyl-1h-pyrazole-3-carboxamidse-am251-reverses-the-hypothermic-effects-of-cannabinoid-receptor-one-agonism-by-1-naphthalenyl
#4
Gareth Pryce, David Baker
BACKGROUND & PURPOSE: Cannabis is a recreational drug leading to intoxication, due to cannabinoid receptor one (CB1 ) stimulation. However, more recently herbs mixed with synthetic cannabinoids sometimes known as "Spice" and "Black Mamba" have been increasing used and their high CB1 receptor affinity means not only marked intoxication, but life-threatening complications and an increasing number of deaths. Whilst many studies have indicated that prophylactic CB1 receptor antagonism can block cannabimimetic effects in animals and humans...
August 11, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28797724/the-effect-of-newly-synthesized-progesterone-derivatives-on-apoptotic-and-angiogenic-pathway-in-mcf-7-breast-cancer-cells
#5
Shaymaa M M Yahya, Abdou O Abdelhamid, Mervat M Abd-Elhalim, Ghada H Elsayed, Emad F Eskander
Due to its high potency and selectivity, anticancer agents consisting of combined molecules have gained great interests. The current study introduces newly synthesized progesterone derivatives of promising anticancer effect. Moreover, the pro-apoptotic and anti-angiogenic effects of these compounds were studied extensively. Several thiazole, pyridine, pyrazole, thiazolopyridine and pyrazolopyridine progesterone derivatives were synthesized. The structure of the novel progesterone derivatives was elucidated and confirmed using the analytical and spectral data...
August 8, 2017: Steroids
https://www.readbyqxmd.com/read/28796502/sky-blue-emitting-iridium-iii-complexes-bearing-nonplanar-tetradentate-chromophore-and-bidentate-ancillary
#6
Yu-Sian Li, Jia-Ling Liao, Ke-Ting Lin, Wen-Yi Hung, Shih-Hung Liu, Gene-Hsiang Lee, Pi-Tai Chou, Yun Chi
Tetradentate chelates bearing tripodal arranged terpyridine and a functional pyrazole unit (i.e., L1-H and L2-H) were employed in preparation of Ir(III) complexes [Ir(L1)Cl2] (1) and [Ir(L2)Cl2] (2); subsequent chloride-to-bipyrazolate substitution gave [Ir(L1)(bipz)] (3) and [Ir(L2)(bipz)] (4). Single-crystal X-ray structural studies on 1 and 3 showed the possession of a tetradentate chelate, whereas the remaining cis-sites are occupied by either dual chlorides or the bipz chelate, respectively. Sky blue organic light-emitting diode with peak efficiencies (10...
August 10, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28795536/corrigendum-sustainable-gel-electrolyte-containing-pyrazole-as-corrosion-inhibitor-and-dendrite-suppressor-for-aqueous-zn-limn2-o4-battery
#7
Tuan K A Hoang, The Nam Long Doan, Julie Hyeonjoo Cho, Jane Ying Jun Su, Christine Lee, Changyu Lu, P Chen
No abstract text is available yet for this article.
August 10, 2017: ChemSusChem
https://www.readbyqxmd.com/read/28792072/synthesis-of-some-novel-2-6-disubstituted-pyridazin-3-2h-one-derivatives-as-analgesic-anti-inflammatory-and-non-ulcerogenic-agents
#8
Tamer H Ibrahim, Yasser M Loksha, Hosam A Elshihawy, Dina M Khodeer, Mohamed M Said
Some novel 2,6-disubstituted pyridazine-3(2H)-one derivatives were synthesized and evaluated for in vitro cyclooxygenase-2 (COX-2) inhibitory efficacy. Compounds 2-{[3-(2-methylphenoxy)-6-oxopyridazin-1(6H)-yl]methyl}-1H-isoindole-1,3(2H)-dione (5a), 2-propyl-6-(o-tolyloxy)pyridazin-3(2H)-one (6a), and 2-benzyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one (16a) showed the most potent COX-2 inhibitory activity with IC50 values of 0.19, 0.11, and 0.24 μM, respectively. The synthesized compounds with the highest COX-2 selectivity indices were evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities...
August 9, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28791530/synthesis-of-diverse-n-acyl-pyrazoles-via-cyclocondensation-of-hydrazides-with-formula-see-text-oxeketene-dithioacetal
#9
Bruna Á Pereira, Alcione V de Bastos, Wystan K O Teixeira, Sidnei Moura E Silva, Alex F C Flores, Darlene C Flores
An elegant, efficient, and highly regioselective approach for the synthesis of novel methyl 5-amino-3-(methylthio)-1-differently substituted-1H-pyrazole-4-carboxylates is reported. The procedure involves the cyclocondensation of [Formula: see text]-oxeketene [Formula: see text]-dimethyl acetal building blocks with different alkyl, aryl, and heterocyclic acid hydrazides. The novel molecules were obtained in good yields and their identities confirmed by NMR and HRMS spectrometry.
August 8, 2017: Molecular Diversity
https://www.readbyqxmd.com/read/28790146/cyp1a1-mediated-intramolecular-rearrangement-of-aminoazepane-in-gdc-0339
#10
Ryan H Takahashi, Xiaojing Wang, Nathaniel L Segraves, Jing Wang, Jae H Chang, Siamak Cyrus Khojasteh, Shuguang Ma
GDC-0339 is a novel small molecule pan-Pim kinase inhibitor that was discovered as a potential treatment for multiple myeloma. During the in vitro and in vivo metabolite profiling of GDC-0339, a metabolite was detected that had the same elemental composition as the parent but was distinct based on chromatographic separation and mass spectrometric fragmentation pattern. High resolution MS/MS data indicated the metabolite was modified at the aminoazepane moiety. The structure was solved by NMR analysis of the isolated metabolite and further confirmed by comparing it to a synthetic standard...
August 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28777332/high-solid-fluorescence-of-a-pyrazoline-derivative-through-hydrogen-bonding
#11
Liang Zhang, Jie Liu, Junkuo Gao, Feng Zhang, Liang Ding
Pyrazoline and its derivatives often exhibit strong emissions in dilute solutions, but their emission intensity is often dramatically reduced in the solid state due to strong intermolecular interactions between neighboring molecules. In this report, we successfully synthesized a new pyrazoline 4-(3-(4-(decyloxy)phenyl)-1-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-N,N-diethylaniline (PPDPD), into which seven fluorine (F) atoms were incorporated. In the solid state, PPDPD emits a strong blue light at λmax 430 nm with a fluorescence quantum yield of up to 41...
August 4, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28772160/design-synthesis-and-biological-evaluation-of-some-novel-benzothiazole-benzoxazole-and-or-benzimidazole-derivatives-incorporating-a-pyrazole-scaffold-as-antiproliferative-agents
#12
Mohamed A Abdelgawad, Rania B Bakr, Hany A Omar
In an aim at developing new antiproliferative agents, new series of benzothiazole/benzoxazole and/or benzimidazole substituted pyrazole derivatives 11a-c, 12a-c and 13a-c were prepared and evaluated for their antiproliferative activity against breast carcinoma (MCF-7) and non-small cell lung cancer (A549) cell lines. The target compound, 2-acetyl-4-[(3-(1H-benzimidazol-2-yl)-phenyl]-hydrazono-5-methyl-2,4-dihydropyrazol-3-one (12a) was the most active compound against both MCF-7 and A549 cell lines with half maximal inhibitory concentrations (IC50)=6...
July 15, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28763211/ligand-design-toward-multifunctional-substrate-reductive-transformations
#13
Alexander V Polezhaev, Chun-Hsing Chen, Adam S Kinne, Alyssa C Cabelof, Richard L Lord, Kenneth G Caulton
The synthesis of bis(N1-phenyl-5-hydroxypyrazol-3-yl)pyridines ("L") is described, and these are silylated to achieve analogues ("Si2L") without the variable of the hydroxyl proton mobility. One hydroxyl example is characterized in its bis-pincer iron(II) complex, which shows every OH proton involved in hydrogen bonding. The steric bulk of the silylated N-phenyl-substituted ligands allows the synthesis and characterization of paramagnetic (Si2L)FeCl2 complexes, and one of these is reduced, under CO, to give the diamagnetic (Si2L)Fe(CO)2 species...
August 1, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28760974/structural-basis-of-subunit-selectivity-for-competitive-nmda-receptor-antagonists-with-preference-for-glun2a-over-glun2b-subunits
#14
Genevieve E Lind, Tung-Chung Mou, Lucia Tamborini, Martin G Pomper, Carlo De Micheli, Paola Conti, Andrea Pinto, Kasper B Hansen
NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A-D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B...
August 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28759231/discovery-of-novel-and-highly-selective-inhibitors-of-calpain-for-the-treatment-of-alzheimer%C3%A2-s-disease-2-3-phenyl-1h-pyrazol-1-yl-nicotinamides
#15
Andreas Kling, Katja Jantos, Helmut Mack, Wilfried Hornberger, Karla Drescher, Volker Nimmrich, Ana Relo, Karsten Wicke, Charles W Hutchins, Yanbin Lao, Kennan C Marsh, Achim Moeller
Calpain overactivation has been implicated in a variety of pathological disorders including ischemia/reperfusion injury, cataract formation, and neurodegenerative diseases such as Alzheimer´s Disease (AD). Herein we describe our efforts leading to the identification of ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as potent and reversible inhibitors of calpain with high selectivity versus related cysteine protease cathepsins, other proteases and receptors. Broad efficacy in a set of preclinical models relevant to AD suggests that inhibition of calpain represents an attractive approach with potential benefit for the treatment of AD...
July 31, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28757050/electroencephalographic-cognitive-and-neurochemical-effects-of-ly3130481-cerc-611-a-selective-antagonist-of-tarp-%C3%AE-8-associated-ampa-receptors
#16
Jeffrey M Witkin, Jennifer Li, Gary Gilmour, Stephen N Mitchell, Guy Carter, Scott D Gleason, Wesley F Seidel, Brian J Eastwood, Andrew McCarthy, Warren J Porter, Jon Reel, Kevin M Gardinier, Akihiko S Kato, Keith A Wafford
6-[(1S)-1-[1-[5-(2-hydroxyethoxy)-2-pyridyl]pyrazol-3-yl]ethyl]-3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) γ-8. This molecule has been characterized as a potent and efficacious anticonvulsant in an array of acute and chronic epilepsy models in rodents. The present set of experiments was designed to assess the effects of LY3130481 on the electroencephelogram (EEG), cognitive function, and neurochemical outflow...
July 27, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28756713/coumarinderivatives-an-updated-patent-review-2015-2016
#17
Anastasia Detsi, Christos Kontogiorgis, Dimitra Hadjipavlou-Litina
INTRODUCTION: Coumarins belong to the benzopyrone family. They are naturally plant-derived or synthetically obtained substances, presenting a wide variety of biological activities, offering an extented therapeutic profile. Their structural characteristics correlated to physicochemical properties define their pleiotropic biological responses. AREAS COVERED IN THIS REVIEW: Recent patent publications (2015-2016), describing coumarins and their derivatives are analyzed...
July 31, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28756138/mutant-p53-as-a-target-for-cancer-treatment
#18
REVIEW
Michael J Duffy, Naoise C Synnott, John Crown
TP53 (p53) is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumours. However, in some of the most difficult-to-treat cancers such as high-grade serous ovarian cancers, triple-negative breast cancers, oesophageal cancers, small-cell lung cancers and squamous cell lung cancers, p53 is mutated in at least 80% of samples. Clearly, therefore, mutant p53 protein is an important candidate target against which new anticancer treatments could be developed...
July 27, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28755439/alpha-oxo-ketenimines-from-isocyanides-and-alpha-haloketones-synthesis-and-divergent-reactivity
#19
Mathias Mamboury, Qian Wang, Jieping Zhu
The palladium-catalyzed reaction of alpha-haloketones with isocyanides afforded alpha-oxo-ketenimines through beta-hydride elimination of the beta-oxo-imidoyl palladium intermediates. Reaction of these relatively stable alpha-oxo-ketenimines with nucleophiles such as hydrazines, hydrazoic acid, amines, and Grignard reagent afforded pyrazoles, tetrazole, beta-keto amidines and enaminone, respectively, with high chemoselectivity. While amines attack exclusively on the ketenimine functions, the formal [3+2] cycloaddition between N-monosubstituted hydrazines and alpha-oxo-ketenimines was initiated by nucleophilic addition to the carbonyl group...
July 29, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28753313/neuroactive-steroids-2-3%C3%AE-hydroxy-3%C3%AE-methyl-21-4-cyano-1h-pyrazol-1-yl-19-nor-5%C3%AE-pregnan-20-one-sage-217-a-clinical-next-generation-neuroactive-steroid-positive-allosteric-modulator-of-the-%C3%AE-aminobutyric-acid-a-receptor
#20
Gabriel Martinez Botella, Francesco G Salituro, Boyd L Harrison, Richard T Beresis, Zhu Bai, Maria-Jesus Blanco, Gabriel M Belfort, Jing Dai, Carlos M Loya, Michael A Ackley, Alison L Althaus, Scott J Grossman, Ethan Hoffmann, James J Doherty, Albert J Robichaud
Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABAA receptors. Herein we report new SAR insights in a series of 5α-nor-19- pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one (SAGE-217, 3), a potent GABAA receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties...
July 28, 2017: Journal of Medicinal Chemistry
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