- New H-bond accepting tris(pyrazolyl)borates: Stabilization of metal aquo species as models for the vicinal oxygen chelate enzyme superfamily
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The hydrogen-bond accepting ligand K[TpCO2Et,Me] was prepared and its complexes with divalent Ni, Co, Mn and Cu reveal a stabilization of penta- or hexa-coordinate metal aquo complexes of the general form [Tp CO2Et,MeM(H2O)x](x = 2 or 3) which are unprecedented for the alkyl substituted Tp analogs. These complexes make good structural models for many of the enzymes of the vicinal oxygen chelate superfamily.
- Hammes,Carrano,Carrano
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Read Online
- Copper(II) and cobalt(II) complexes of 5-methyl pyrazole-3-carboxylic acid: synthesis, X-ray crystallography, thermal analysis and in vitro antimicrobial activity
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The coordination behavior of 5-methylpyrazole-3-carboxylic acid (Hmpca) has been demonstrated by the solid state isolation and characterization of [Cu(mpca)2(H2O)]·3H2O (1) [Cu(mpca)2]·H2O (2) and [Co(mpca)2(H2O)2] (3). The new compounds are characterized by X-ray crystallography, thermogravimetric analysis and DFT study. The redox properties of the complexes are examined by cyclic voltammetric analysis. The antibacterial and antifungal activities of the compounds against eight bacteria (Escherichia coli, Enterococcus faecalis, Bacillus subtilis, Klebsiella pneumoniae, Proteus vulgaris, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi) and two fungi (Aspergillus flavus and Candida albicans) are screened using modified agar well diffusion method. The metal complexes demonstrate better inhibition on all bacteria and fungi than the ligand. The high lipophilicity of the complexes accounts for good inhibitory action toward microbes. Among the reported complexes, 3 emerges as an excellent antifungal agent and a better antibiotic than standard fluconazole. The structure and activity relationship indicate that complexes having sufficient Jahn–Teller distortion with high logP values, cross the cell membrane of the microbes creating intercellular damage.
- Santra, Ananyakumari,Brandao, Paula,Jana, Harekrishna,Mondal, Gopinath,Bera, Pradip,Jana, Abhimanyu,Bera, Pulakesh
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Read Online
- A novel pyrazole based single molecular probe for multi-analyte (Zn2+ and Mg2+) detection in human gastric adenocarcinoma cells
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A new fluorescent sensor, 5-methyl-1H-pyrazole-3-carboxylic acid (6-methoxy-naphthalen-2-ylmethylene)-hydrazide (PYN), composed of a naphthalene group as the fluorogenic unit and a pyrazole carbohydrazide as the binding unit for metal ions has been designed and synthesized. The sensor shows excellent selectivity and sensitivity with a fluorescence enhancement towards Zn2+ and Mg2+ over other cations in aqueous acetonitrile solution. Turn-on fluorescent enhancements (FE) as high as ~49 fold and ~41 fold in mixed media for Zn2+ and, Mg2+ respectively were noticed. The signal enhancement of the sensor is based on chelation-enhanced fluorescence (CHEF) effect of PYN-Zn2+/Mg2+ with the inhibition of the photoinduced electron transfer (PET) effect. Moreover, the Job's plot established 1?:?1 stoichiometry of the complex formation between PYN and Zn2+ or Mg2+ ions. The limit of detection for Zn2+ and Mg2+ is as low as 2.2 × 10?7 M and 3.9 × 10?7 M respectively. PYN exhibited a second mode of selectivity for Zn2+ as it displaces Mg2+ from the PYN-Mg2+ complex. Density Functional Theory (DFT) calculations have been performed in order to show the structure and electronic properties of PYN and its complexes [PYN-Zn2+/Mg2+]. Cell imaging experiments confirmed that PYN can be used for monitoring intracellular Zn2+ and Mg2+ levels in living cells in vitro.
- Dhara, Anamika,Guchhait, Nikhil,Mukherjee, Indrani,Mukherjee, Abhishek,Chandra Bhattacharya, Subhash
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p. 105930 - 105939
(2016)
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Read Online
- Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies
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Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
- Soares De Melo, Candice,Singh, Vinayak,Myrick, Alissa,Simelane, Sandile B.,Taylor, Dale,Brunschwig, Christel,Lawrence, Nina,Schnappinger, Dirk,Engelhart, Curtis A.,Kumar, Anuradha,Parish, Tanya,Su, Qin,Myers, Timothy G.,Boshoff, Helena I. M.,Barry, Clifton E.,Sirgel, Frederick A.,Van Helden, Paul D.,Buchanan, Kirsteen I.,Bayliss, Tracy,Green, Simon R.,Ray, Peter C.,Wyatt, Paul G.,Basarab, Gregory S.,Eyermann, Charles J.,Chibale, Kelly,Ghorpade, Sandeep R.
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p. 719 - 740
(2021/02/03)
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- COMBINATION TREATMENTS COMPRISING ADMINISTRATION OF 1H-PYRAZOLO[4,3-B]PYRIDINES
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The present invention provides 1H-pyrazolo[4,3-b]pyridin-7-amines of formula (I) as PDE1 inhibitors together with a second compound useful in the treatment of a neurodegenerative disorder and their combined use as a medicament, in particular for the treatment of neurodegenerative and/or cognitive disorders.
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Page/Page column 84
(2019/07/19)
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- MACROCYCLES AS PDE1 INHIBITORS
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The present invention provides macrocycles of formula (I) as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.
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Paragraph 0111; 0112
(2019/06/30)
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- 1H-PYRAZOLO[4,3-B]PYRIDINES AS PDE1 INHIBITORS
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The present invention provides 1H-pyrazolo[4,3-b]pyridines of formula (I) as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.
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Paragraph 0365-0366
(2019/07/10)
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- COMBINATION TREATMENTS COMPRISING ADMINISTRATION OF 1H-PYRAZOLO[4,3-B]PYRIDINES
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The present invention provides 1H-pyrazolo[4,3-b]pyridin-7-amines of formula (I) as PDE1 inhibitors together with a second compound which compound is useful in the treatment of a psychiatric disorder and their combined use as a medicament, in particular for the treatment of psychiatric and/or cognitive disorders.
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Page/Page column 81
(2019/07/19)
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- Design, synthesis, antifungal activity and 3D-QSAR study of novel pyrazole carboxamide and niacinamide derivatives containing benzimidazole moiety
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A series of novel pyrazole carboxamide and niacinamide derivatives containing a benzimidazole moiety were designed and synthesized as antifungal candidate agents. All target compounds were characterized by FTIR, 1H NMR, 13C NMR, HRMS and elemental analysis techniques. The structure of compound T1 was further confirmed by single crystal X-ray diffraction analysis. The antifungal activities of the target compounds were evaluated in vitro against four phytopathogenic fungi (namely Botrytis cinerea, Rhizoctonia solani, Fusarium graminearum and Alternaria solani) by the mycelium growth inhibition method. The bioassay results indicated that some of the compounds exhibited good antifungal activity against B. cinerea at 100 μg ML?1 compared to other three fungi. In order to better explore the structure-activity relationship (SAR), the EC50 values of target compounds against B. cinerea were measured and assessed. Subsequently, a 3D quantitative structure-activity relationship (3D-QSAR) study was carried out using the comparative molecular field analysis (CoMFA) technique based on the inhibitory activities of tested compounds against B. cinerea. Molecular modelling results revealed fine predictive ability with cross-validated q2 and non-cross-validated r2 values of 0.578 and 0.850, respectively.
- Si, Wei-Jie,Wang, Xiao-Bin,Chen, Min,Wang, Meng-Qi,Lu, Ai-Min,Yang, Chun-Long
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p. 3000 - 3010
(2019/02/17)
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- 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile synthesis method
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The invention belongs to the technical field of medicine and relates to a 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile synthesis method. Diethyl oxalate and acetone are easily acquirable andused as starting materials to obtain 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile through 7-step reaction including condensation, cyclization, methylation, amidation, oxidation, brominationand amination. By adoption of the method, preparation of 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile which is a key intermediate of antitumor drug lorlatinib (PF-06463922) is realized, thetotal yield reaches 5.7% or above, and simplicity in operation, convenience in aftertreatment, short time consumption and low cost are realized while industrialization can be realized beneficially. The intermediate and 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone are subjected to reaction steps including ammonolysis, substitution, coupling, chiral resolution and the like to finally synthesize lorlatinib, and a novel method is provided for synthesis of the antitumor drug lorlatinib.
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Paragraph 0024; 0028-0030
(2019/01/14)
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- 1H-PYRAZOLO[4,3-B]PYRIDINES AS PDE1 INHIBITORS
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The present invention provides 1H-pyrazolo[4,3-b]pyridin-7-amines of formula (I) as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.
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Page/Page column 75
(2018/09/25)
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- Design, synthesis, DFT study and antifungal activity of the derivatives of pyrazolecarboxamide containing thiazole or oxazole ring
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Pyrazolecarboxamide fungicides are one of the most important classes of agricultural fungicides, which belong to succinodehydrogenase inhibitors (SDHIS). To discover new pyrazolecarboxamide analogues with broad spectrum and high activity, a class of new compounds of pyrazole carboxamide derivatives containing thiazole or oxazole ring were designed by scaffold hopping and bioisosterism, and 36 pyrazole carboxamide derivatives with antifungal activity were synthesized. Those compounds were evaluated against five phytopathogenic fungi, Gibberella zeae, Phytophythora capsici, Sclerotonia sclerotiorum, Erysiphe graminis and Puccinia sorghi. The results indicated that most of the compounds displayed good fungicidal activities, especially against E. graminis. Theoretical calculations were carried out at the B3LYP/6-31G (d, p) level and the full geometry optimization was carried out using the 6-31G (d, p) basis set, and the frontier orbital energy, atomic net charges, molecular docking were discussed, and the structure-activity relationships were also studied.
- Yan, Zhongzhong,Liu, Aiping,Huang, Mingzhi,Liu, Minhua,Pei, Hui,Huang, Lu,Yi, Haibo,Liu, Weidong,Hu, Aixi
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p. 170 - 181
(2018/03/08)
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- Design, Synthesis, and Acaricidal Activities of Novel Pyrazole Acrylonitrile Compounds
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Using cyenopyrafen as the lead compound, a series of novel pyrazole acrylonitrile compounds were designed and synthesized via the reaction of butylphenylacetonitrile with the corresponding (substituted pyrazol-5-yl) methanone of pyrethroid alcohols in the presence of potassium tert-butoxide. These compounds showed prominent acaricidal activity against Tetranchus urticae. In particular, IIf, IIh, IIo, and IIp displayed excellent activities, which the median lethal concentrations were all lower 0.4 mg/L. In addition, the structure-activity relationship for the target compounds was discussed.
- Huang, Danling,Huang, Mingzhi,Liu, Aiping,Liu, Xingping,Liu, Weidong,Chen, Xiaoyang,Xue, Hansong,Sun, Jiong,Yin, Dulin,Wang, Xiaoguang
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p. 1121 - 1128
(2017/03/27)
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- Pyrazole amide compound, and preparation method and application thereof
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The invention discloses a pyrazole amide compound represented by the formula (I), and a preparation method and an application thereof, wherein R, R1, R2 and W have the definitions indicated in the specification. The compound represented by the formula (I) has bactericidal, insecticidal or acaricidal biological activities, and specially has quite high activity on pathogenic bacteria such as sphaerotheca fuliginea, botrytis cinerea, melampsora lini and the like.
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Paragraph 0101-0103
(2017/06/02)
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- Preparation method of tolfenpyrad impurity
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The invention discloses a preparation method of N-[4-(4-methylphenoxy)benzyl]-1,3,4-trimethyl-5-pyrazole-carboxamide disclosed as a chemical structural formula I. In methylation reaction for preparing ethyl 1,3-dimethyl-5-pyrazole formate, dimethyl carbonate is adopted as a methylating agent; cesium carbonate is adopted as a catalyst; in the process of preparing ethyl 1,3,4-trimethyl-5-pyrazole formate, the ethyl 1,3-dimethyl-5-pyrazole formate is subjected to chloromethylation and catalytic hydrogenolysis to obtain the ethyl 1,3,4-trimethyl-5-pyrazole formate; and in acyl-chlorination reaction of 1,3,4-trimethyl-5-pyrazole formic acid, triphosgene is used as an acyl-chlorination agent, which is green and environment-friendly.
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Paragraph 0019; 0022; 0023
(2017/10/13)
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- A new class of phenylhydrazinylidene derivatives as inhibitors of Staphylococcus aureus biofilm formation
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In the struggle against the emergence of the antibiotic resistance, new molecules targeting biofilm formation could be useful as adjuvant of conventional antibiotics. This study focused on a new class of 2-phenylhydrazinylidene derivatives as antivirulence agents. The compound 12e showed interesting activities against biofilm formation of all tested Staphylococcus aureus strains with IC50 ranging from 1.7 to 43 μM; compounds 12f and 13a resulted strong inhibitors of S. aureus ATCC 6538 and ATCC 29213 biofilm formation with IC50 of 0.9 and 0.8 μM, respectively. A preliminary study on the mechanism of action was carried on evaluating the inhibition of sortase A transpeptidase. Compound 12e resulted not to be toxic at 1 mg/ml by using an in vivo model (the wax moth larva model, Galleria mellonella).
- Cascioferro, Stella,Maggio, Benedetta,Raffa, Demetrio,Raimondi, Maria Valeria,Cusimano, Maria Grazia,Schillaci, Domenico,Manachini, Barbara,Leonchiks, Ainars,Daidone, Giuseppe
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p. 870 - 878
(2016/04/20)
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- Synthesis, characterization and antibacterial activity of novel Schiff bases
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The present work describes the synthesis of novel Schiff bases (8.1-8.9) in five steps from diethyl oxalate and acetone as starting materials. Condensation of ethyl 1-(2-aminophenyl)-5-methyl-1H-pyrazole-3-carboxylate (6) with aromatic and heteroaromatic aldehydes (7.1-7.9) in presence of sodium sulphate at 50 °C in ethanol gave the corresponding imine derivatives (8.1-8.9) in quantitative yields. The structure of these compounds was determined by 1H NMR, mass and IR spectral data. These Schiff's bases were further evaluated for antibacterial activity against the selected Gram-positive and Gram-negative bacteria pathogens. The antibacterial activity data revealed that Schiff base embedded with heteroaromatic ring was found to exhibit good antibacterial activity than the aromatic ring.
- Sreedhar, Pandiri,Srinivas, Gudipati,Raju, Rallabandi Madhusudan
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p. 1603 - 1606
(2016/05/09)
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- NOVEL PYRROLIDINE DERIVED BETA 3 ADRENERGIC RECEPTOR AGONISTS
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The present invention provides compounds of Formula (I), pharmaceutical compositions thereof, and method of using the same in the treatment or prevention of diseases mediated by the activation of β3-adrenoceptor.
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Page/Page column 52; 53
(2015/04/22)
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- Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity
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Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.
- Bruncko, Milan,Wang, Le,Sheppard, George S.,Phillips, Darren C.,Tahir, Stephen K.,Xue, John,Erickson, Scott,Fidanze, Steve,Fry, Elizabeth,Hasvold, Lisa,Jenkins, Gary J.,Jin, Sha,Judge, Russell A.,Kovar, Peter J.,Madar, David,Nimmer, Paul,Park, Chang,Petros, Andrew M.,Rosenberg, Saul H.,Smith, Morey L.,Song, Xiaohong,Sun, Chaohong,Tao, Zhi-Fu,Wang, Xilu,Xiao, Yu,Zhang, Haichao,Tse, Chris,Leverson, Joel D.,Elmore, Steven W.,Souers, Andrew J.
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supporting information
p. 2180 - 2194
(2015/03/30)
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- N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase
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High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors.
- Pelcman, Benjamin,Sanin, Andrei,Nilsson, Peter,Schaal, Wesley,Olofsson, Kristofer,Krog-Jensen, Christian,Forsell, Pontus,Hallberg, Anders,Larhed, Mats,Boesen, Thomas,Kromann, Hasse,Claesson, Hans-Erik
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p. 3017 - 3023
(2015/06/22)
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- On water synthesis of N-unsubstituted pyrazoles: Semicarbazide hydrochloride as an alternative to hydrazine for preparation of pyrazole-3-carboxylate derivatives and 3,5-disubstituted pyrazoles
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A green, simple and highly efficient method for the synthesis of pyrazole-3-carboxylates and 3,5-disubstituted pyrazoles by cyclization of 4-aryl(hetaryl, alkyl)-2,4-diketoesters and 1,3-diketones with semicarbazide hydrochloride under on water conditions has been developed. This method also does not require toxic hydrazine and product purification, eliminating the use of toxic liquid chemicals.
- Markovi, Violeta,Joksovi, Milan D.
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supporting information
p. 842 - 847
(2015/03/04)
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- Pyrazole-oxadiazole conjugates: Synthesis, antiproliferative activity and inhibition of tubulin polymerization
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A number of pyrazole-oxadiazole conjugates were synthesized and evaluated for their ability to function as antiproliferative agents on various human cancer cell lines. These conjugates are comprised of pyrazole and oxadiazole scaffolds closely attached to each other without any spacer as two structural classes. The Type I class has a trimethoxy substituent and the type II class has a 3,4-(methylenedioxy) substituent on their A rings. Among these conjugates, 11a, 11d and 11f manifest potent cytotoxicity with IC50values ranging from 1.5 μM to 11.2 μM and inhibit tubulin polymerization with IC50values of 1.3 μM, 3.9 μM and 2.4 μM respectively. The cell cycle assay showed that treatment with these conjugates results in accumulation of cells in the G2/M phase and disrupts the microtubule network. Elucidation of zebrafish embryos revealed that the conjugates cause developmental defects. Molecular docking simulations determined the binding modes of these potent conjugates at the colchicine site of tubulin.
- Kamal, Ahmed,Shaik, Anver Basha,Polepalli, Sowjanya,Santosh Reddy, Vangala,Bharath Kumar,Gupta, Soma,Rama Krishna,Nagabhushana, Ananthamurthy,Mishra, Rakesh K.,Jain, Nishant
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p. 7993 - 8007
(2015/02/18)
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- Structure-activity relationships of pyrazole derivatives as potential therapeutics for immune thrombocytopenias
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Idiopathic or immune thrombocytopenia (ITP) is a serious clinical disorder involving the destruction of platelets by macrophages. Small molecule therapeutics are highly sought after to ease the burden on current therapies derived from human sources. Earlier, we discovered that dimers of five-membered heterocycles exhibited potential to inhibit phagocytosis of human RBCs by macrophages. Here, we reveal a structure-activity relationship of the bis-pyrazole class of molecules with -C-C-, -C-N- and -C-O- linkers, and their evaluation as inhibitors of phagocytosis of antibody-opsonized human RBCs as potential therapeutics for ITP. We have uncovered three potential candidates, 37, 47 and 50, all carrying a different linker connecting the two pyrazole moieties. Among these compounds, hydroxypyrazole derivative 50 is the most potent compound with an IC50 of 14 ± 9 μM for inhibiting the phagocytosis of antibody-opsonized human RBCs by macrophages. None of the compounds exhibited significant potential to induce apoptosis in peripheral blood mononuclear cells (PBMCs). Current study has revealed specific functional features, such as up to 2-atom spacer arm and alkyl substitution at one of the N1 positions of the bivalent pyrazole core to be important for the inhibitory activity.
- Purohit, Meena K.,Chakka, Sai Kumar,Scovell, Iain,Neschadim, Anton,Bello, Angelica M.,Salum, Norue,Katsman, Yulia,Bareau, Madeleine C.,Branch, Donald R.,Kotra, Lakshmi P.
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p. 2739 - 2752
(2014/05/06)
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- PYRAZOLE DERIVATIVES AND THEIR USES THEREOF
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The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein U, R1, R2, R3 and Q are as defined herein. The disclosure also provides a method for treating or preventing a method for the prevention, treatment and/or alleviation of one or more autoimmune or alloimmune disease, pharmaceutical compositions and combination comprising a therapeutically effective amount of a compound, as defined herein.
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Page/Page column 17; 18
(2014/09/29)
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- Highly regioselective organocatalyzed synthesis of pyrazoles from diazoacetates and carbonyl compounds
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A general, organocatalytic inverse-electron-demand [3+2] cycloaddition reaction between a range of carbonyl compounds and diazoacetates has been developed. This reaction is catalyzed by secondary amines as a "green promoter" to generate substituted pyrazoles with high levels of regioselectivity. It is noteworthy that this [3+2] cycloaddition reaction proceeds efficiently at room temperature with a simple and inexpensive catalyst. Considering the large variety and ready availability of the starting materials (e.g. ketones, β-ketoesters, β-diketones, and aldehydes), as well as the operational simplicity of this process, a convenient, practical, and highly modular pyrazole synthesis has been developed. We believe that this work will arouse more research interest in the organocatalytic synthesis of other biologically active heterocycles. Such studies are currently underway in our laboratory. Dipoles apart: In situ formed enamines react with diazoacetates under mild conditions to afford the corresponding polysubstituted pyrazoles in good-to-excellent yields through an inverse-electron-demand 1,3-dipolar cycloaddition process (see scheme). Copyright
- Wang, Lei,Huang, Jiayao,Gong, Xiaojie,Wang, Jian
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supporting information
p. 7555 - 7560
(2013/07/05)
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- Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain l-2-hydroxy acid oxidase
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Long chain l-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.
- Barawkar, Dinesh A.,Bandyopadhyay, Anish,Deshpande, Anil,Koul, Summon,Kandalkar, Sachin,Patil, Pradeep,Khose, Goraksha,Vyas, Samir,Mone, Mahesh,Bhosale, Shubhangi,Singh, Umesh,De, Siddhartha,Meru, Ashwin,Gundu, Jayasagar,Chugh, Anita,Palle, Venkata P.,Mookhtiar, Kasim A.,Vacca, Joseph P.,Chakravarty, Prasun K.,Nargund, Ravi P.,Wright, Samuel D.,Roy, Sophie,Graziano, Michael P.,Cully, Doris,Cai, Tian-Quan,Singh, Sheo B.
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scheme or table
p. 4341 - 4347
(2012/07/17)
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- COMPOUNDS AS HSP90 INHIBITORS
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The invention provides novel compounds of formula (I) wherein: one of the a, b, c or d members is a nitrogen atom and the remaining members are carbon atoms; and R3 is a radical selected from the group consisting of: —S—R14 and —CH2—R15. The compounds of formula (I) are useful for treating diseases mediated by a heat shock protein 90 (Hsp 90)
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Page/Page column 80
(2009/03/07)
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- 1,3-Dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives as highly potent and selective human A2B adenosine receptor antagonists
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A new series of 1,3-dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives has been identified as potent A2B adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A2B, A1, A2A, and A3 adenosine receptors. N-(4-chloro-phenyl)-2-[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl] (11c) showed a high affinity for the human A2B adenosine receptor Ki = 7 nM and good selectivity (A1, A2A, A3/A2B > 140). Synthesis and SAR of this novel class of compounds is presented herein.
- Tabrizi, Mojgan Aghazadeh,Baraldi, Pier Giovanni,Preti, Delia,Romagnoli, Romeo,Saponaro, Giulia,Baraldi, Stefania,Moorman, Allan R.,Zaid, Abdel Naser,Varani, Katia,Borea, Pier Andrea
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p. 2419 - 2430
(2008/09/21)
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- Fluorinated pyrazole acids are agonists of the high affinity niacin receptor GPR109a
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A series of 5-alkyl pyrazole-3-carboxylic acids were prepared and found to act as potent and selective agonists of the human GPCR, GPR109a, the high affinity nicotinic acid receptor. No activity was observed at the highly homologous low affinity niacin receptor, GPR109b. A further series of 4-fluoro-5-alkyl pyrazole-3-carboxylic acids were shown to display similar potency. One example from the series was shown to have improved properties in vivo compared to niacin.
- Skinner, Philip J.,Cherrier, Martin C.,Webb, Peter J.,Shin, Young-Jun,Gharbaoui, Tawfik,Lindstrom, Andrew,Hong, Vu,Tamura, Susan Y.,Dang, Huong T.,Pride, Cameron C.,Chen, Ruoping,Richman, Jeremy G.,Connolly, Daniel T.,Semple, Graeme
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p. 5620 - 5623
(2008/04/02)
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- PYRAZOLE COMPOUNDS USEFUL IN THE TREATMENT OF INFLAMMATION
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There is provided compounds of formula (I), wherein R1, R2, Ra and Rb have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a lipoxygenase (e.g. 15-lipoxygenase) is desired and/or required, and particularly in the treatment of inflammation.
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Page/Page column 39
(2010/10/20)
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- Sildenafil (Viagra(TM)), a potent and selective inhibitor of type 5 CGMP phosphodiesterase with utility for the treatment of male erectile dysfunction
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5-(2'-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRA(TM)), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.
- Terrett, Nicholas K.,Bell, Andrew S.,Brown, David,Ellis, Peter
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p. 1819 - 1824
(2007/10/03)
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- One-pot synthesis of 3(5)-ethoxycarbonylpyrazoles
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A one-pot synthesis of ethoxycarbonylpyrazoles 2a-e, by the cyclocondensation of β-alkoxyvinyl trichloromethyl ketones 1a-e with hydrazine hydrochloride under mild conditions, is reported. A study using compounds 1a-e with different substituents proved that these are versatile building blocks for the synthesis of pyrazole derivatives, having a 3(5)-ethoxycarbonyl substituent, in good yields (70-91%).
- Martins,Freitag,Flores,Zanatta
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p. 1491 - 1492
(2007/10/02)
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- Reaction of Carbonyl Compounds with Ethyl Lithiodiazoacetate. Studies Dealing with the Rhodium(II)-Catalyzed Behavior of the Resulting Adducts
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The carbenoid intermediate derived by treating ethyl 2-diazo-4-phthalimidobutyrate with rhodium(II) octanoate undergoes transannular cyclization onto the adjacent imido carbonyl group.The resulting cyclic carbonyl ylide diploe was trapped with several dipolarophiles.In an attempt to prepare related substrates for cyclization studies, the reaction of ethyl lithiodiazoacetate with various aldehydes and ketones was studied.Treatment of the α-diazo-β-hydroxy ester derived from acetone or cyclopentanone with rhodium(II) octanoate gave rise to a β-keto ester.The exclusive phenyl shift encountered with acetophenone is in keeping with migration to an electron-deficient center.The reaction works well with acrolein, leading to high yields of 3-oxo-4-pentenoate.The 1,2-hydrogen shift pathway was found to proceed much faster than intramolecular cyclopropanation.Dehydration of the α-diazo-β-hydroxy esters generates vinyl diazo esters, which readily cyclize to 1H-pyrazoles on thermolysis.
- Padwa, Albert,Kulkarni, Yashwant S.,Zhang, Zhijia
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p. 4144 - 4153
(2007/10/02)
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- Effective Methods for the Syntheses of 2-Pyrazolines and Pyrazoles from Diazocarbonyl Compounds
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Dipolar addition of diazocarbonyl compounds to α,β-unsaturated esters and nitriles in the presence of pyridine results in the production 2-pyrazolines in nearly quantitative yields.In one case, reaction of α-diazoacetophenone with acrylonitrile, Michael addition of the 2-pyrazoline to the conjugated olefin is observed, but this process is minimized by limiting the amount of pyridine employed. 5-Cyano-2-pyrazolines are converted to derivative pyrazoles through alkoxide promoted hydrogen cyanide elimination.With vinyl sulfone, α-diazoacetophenone undergoes sequential dipolar addition, Michael addition, and vinyl sulfite elimination under exceptionally mild conditions to form the derivative β-(1-pyrazolyl)ethyl vinyl sulfone in good yield.
- Doyle, Michael P.,Colsman, Mark R.,Dorow, Roberta L.
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p. 943 - 946
(2007/10/02)
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