- Large-scale synthesis of a key catalytic reagent for phosphorus protection in building blocks for isopolar phosphonate oligonucleotide preparation
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A simple procedure for the large-scale synthesis of 4-methoxy-2-pyridinemethanol 1-oxide (5), a key compound in modern triester synthesis of oligonucleotides, employing Buechi R 152 evaporator as a reaction apparatus was elaborated. Two crucial reaction steps, both strongly exothermic, were satisfactorily handled. Our procedure provides a high-purity, light-and heat-stable product in a satisfactory yield.
- Rejman, Dominik,Erbs, Jiri,Rosenberg, Ivan
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Read Online
- Stable and rigid DTPA-like paramagnetic tags suitable for in vitro and in situ protein NMR analysis
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Organic synthesis of a ligand with high binding affinities for paramagnetic lanthanide ions is an effective way of generating paramagnetic effects on proteins. These paramagnetic effects manifested in high-resolution NMR spectroscopy are valuable dynamic and structural restraints of proteins and protein–ligand complexes. A paramagnetic tag generally contains a metal chelating moiety and a reactive group for protein modification. Herein we report two new DTPA-like tags, 4PS-PyDTTA and 4PS-6M-PyDTTA that can be site-specifically attached to a protein with a stable thioether bond. Both protein-tag adducts form stable lanthanide complexes, of which the binding affinities and paramagnetic tensors are tunable with respect to the 6-methyl group in pyridine. Paramagnetic relaxation enhancement (PRE) effects of Gd(III) complex on protein-tag adducts were evaluated in comparison with pseudocontact shift (PCS), and the results indicated that both 4PS-PyDTTA and 4PS-6M-PyDTTA tags are rigid and present high-quality PREs that are crucially important in elucidation of the dynamics and interactions of proteins and protein-ligand complexes. We also show that these two tags are suitable for in-situ protein NMR analysis.
- Chen, Jia-Liang,Zhao, Yu,Gong, Yan-Jun,Pan, Bin-Bin,Wang, Xiao,Su, Xun-Cheng
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- ANTIBIOTIC COMPOUNDS
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The present invention relates to antibiotic compounds of formula (I), to compositions containing these compounds and to methods of treating bacterial diseases and infections using the compounds. The compounds find application in the treatment of infection with, and diseases caused by, Gram-positive and/or Gram-negative bacteria, and in particular in the treatment of infection with, and diseases caused by, Neisseria gonorrhoeae.
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Page/Page column 175
(2018/03/25)
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- Single-armed phenylsulfonated pyridine derivative of DOTA is rigid and stable paramagnetic tag in protein analysis
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Single-armed DOTA-like phenylsulfonated pyridine derivatives are rigid and stable paramagnetic tags for site-specific labeling of proteins. Their reactions with a solvent-exposed protein thiol group generate a stable C-S bond and produce one single paramagnetic species in solution NMR. The generated large paramagnetic effects yield valuable long-range structural restraints for proteins.
- Yang, Feng,Wang, Xiao,Pan, Bin-Bin,Su, Xun-Cheng
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p. 11535 - 11538
(2016/10/03)
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- Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase
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Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that incorporate a 7-indolizinylamino or 2-naphthylamino substituent on a pyrimidine or 1,3,5-triazine core. The most potent compounds show below 10 nanomolar activity towards wild-type HIV-1 and variants bearing Tyr181Cys and Lys103Asn/Tyr181Cys resistance mutations. The compounds also feature good aqueous solubility. Crystal structures for two complexes enhance the analysis of the structure-activity data.
- Lee, Won-Gil,Frey, Kathleen M.,Gallardo-Macias, Ricardo,Spasov, Krasimir A.,Chan, Albert H.,Anderson, Karen S.,Jorgensen, William L.
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p. 4824 - 4827
(2015/10/28)
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- C-H bond oxidation catalyzed by an imine-based iron complex: A mechanistic insight
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A family of imine-based nonheme iron(II) complexes (LX)2Fe(OTf)2 has been prepared, characterized, and employed as C-H oxidation catalysts. Ligands LX (X = 1, 2, 3, and 4) stand for tridentate imine ligands resulting from spontaneous condensation of 2-pycolyl-amine and 4-substituted-2-picolyl aldehydes. Fast and quantitative formation of the complex occurs just upon mixing aldehyde, amine, and Fe(OTf)2 in a 2:2:1 ratio in acetonitrile solution. The solid-state structures of (L1)2Fe(OTf)(ClO4) and (L3)2Fe(OTf)2 are reported, showing a low-spin octahedral iron center, with the ligands arranged in a meridional fashion. 1H NMR analyses indicate that the solid-state structure and spin state is retained in solution. These analyses also show the presence of an amine-imine tautomeric equilibrium. (LX)2Fe(OTf)2 efficiently catalyze the oxidation of alkyl C-H bonds employing H2O2 as a terminal oxidant. Manipulation of the electronic properties of the imine ligand has only a minor impact on efficiency and selectivity of the oxidative process. A mechanistic study is presented, providing evidence that C-H oxidations are metal-based. Reactions occur with stereoretention at the hydroxylated carbon and selectively at tertiary over secondary C-H bonds. Isotopic labeling analyses show that H2O2 is the dominant origin of the oxygen atoms inserted in the oxygenated product. Experimental evidence is provided that reactions involve initial oxidation of the complexes to the ferric state, and it is proposed that a ligand arm dissociates to enable hydrogen peroxide binding and activation. Selectivity patterns and isotopic labeling studies strongly suggest that activation of hydrogen peroxide occurs by heterolytic O-O cleavage, without the assistance of a cis-binding water or alkyl carboxylic acid. The sum of these observations provides sound evidence that controlled activation of H2O2 at (LX)2Fe(OTf)2 differs from that occurring in biomimetic iron catalysts described to date.
- Olivo, Giorgio,Nardi, Martina,Vìdal, Diego,Barbieri, Alessia,Lapi, Andrea,Gómez, Laura,Lanzalunga, Osvaldo,Costas, Miquel,Di Stefano, Stefano
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p. 10141 - 10152
(2015/11/16)
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- Metal-free methylation of a pyridine N-oxide C-H bond by using peroxides
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Metal-free methylation of a pyridine N-oxide C-H bond was developed using peroxide as a methyl reagent under neat conditions. Pyridine N-oxide derivatives with various groups (e.g., Cl, NO2, and OCH3) were all suitable substrates, and the desired products were obtained in moderate to excellent yields under standard conditions. Moreover, the methylation can be performed with a good yield on the gram-scale experiment. Tentative mechanistic studies show that the methylation is a classical radical process.
- Li, Gang,Yang, Suling,Lv, Bingjie,Han, Qingqing,Ma, Xingxing,Sun, Kai,Wang, Zhiyong,Zhao, Feng,Lv, Yunhe,Wu, Hankui
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supporting information
p. 11184 - 11188
(2015/11/27)
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- Design and synthesis of N-Aryl isothioureas as a novel class of gastric H+/K+-ATPase inhibitors
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To find new H+/K+-ATPase inhibitors for the treatment of peptic ulcer disease, a series of novel N-aryl isothiourea derivatives were synthesized and their structures were identified by 1H NMR and GC-MS. The effects of these compounds on inhibiting gastric acid secretion were evaluated by the guinea pig stomach mucous membrane study with pantoprazole magnesium as a positive control. The results showed that, of the 37 N-aryl isothiourea compounds synthesized, 20 compounds have comparable or stronger gastric acid inhibitory activities than that of pantoprazole magnesium. The quantitative structure-activity relationships (QSARs) of the N-aryl isothiourea compounds were also studied by comparative molecular field analysis (CoMFA) computation, and the model structure that was supposed to give more powerful bioactivities was finally predicted. A series of novel N-aryl isothiourea derivatives were synthesized and evaluated for their effects of inhibiting gastric acid secretion using the guinea pig stomach mucous membrane study with pantoprazole magnesium as a positive control. Compounds 2c, 2e, and 2k have higher bioactivity. The quantitative structure-activity relationships also defined these structural requirements.
- Ma, Chao,Wu, Anhui,Wu, Yongqi,Ren, Xuhong,Cheng, Maosheng
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p. 891 - 900
(2014/01/06)
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- Substituent effects on the catalytic activity of bipyrrolidine-based iron complexes
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The catalytic activity and the selectivity of the new bipyrrolidine-based Fe(II) complexes 2·Fe(OTf)2 and 3·Fe(OTf)2 in the oxidation of a series of alkyl and alkenyl hydrocarbons as well as of an aromatic sulfide with H2O2 were tested and compared with the catalytic efficiency of White's parent complex 1·Fe(OTf)2 in order to evaluate the sensitivity of the reaction to electronic effects.
- Olivo, Giorgio,Lanzalunga, Osvaldo,Mandolini, Luigi,Di Stefano, Stefano
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p. 11508 - 11512
(2013/12/04)
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- Tuning of the properties of transition-metal bispidine complexes by variation of the basicity of the aromatic donor groups
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Bispidines (3,7-diazabicyclo[3.3.1]nonanes) as very rigid and highly preorganized ligands find broad application in the field of coordination chemistry, and the redox potentials of their transition-metal complexes are of importance in oxidation reactions by high-valent iron complexes, aziridination catalyzed by copper complexes, and imaging by 64Cu positron emission tomography tracers. Here, we show that the redox potentials and stability constants of the copper(II) complexes of 15 tetradentate bispidines can be varied by substitution of the pyridine rings (variation of the redox potential over ca. 450 mV and of the complex stability over approximately 10 log units). It is also shown that these variations are predictable by the pKa values of the pyridine groups as well as by the Hammett parameters of the substituents, and the density functional theory based energy decomposition analysis also allows one to accurately predict the redox potentials and concomitant complex stability. It is shown that the main contribution emerges from the electrostatic interaction energy, and the partial charges of the pyridine donor groups therefore also correlate with the redox potentials.
- Comba, Peter,Morgen, Michael,Wadepohl, Hubert
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p. 6481 - 6501
(2013/07/19)
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- Complexes of 4- and 5-bromo derivatives of 2-(hydroxymethyl)pyridine with copper(II) and cobalt(II) salts. Synthesis and X-ray crystal structures
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Four copper(II) complexes (1-4) and a cobalt(II) complex (5) derived from 4-bromo-2-(hydroxymethyl)pyridine (L1) or 5-bromo-2-hydroxymethyl)pyridine (L2) with Cu(NO3)2·3H2O, CuCl2·2H2O and CoCl2·6H2O have been synthesized and their respective crystal structures studied. They show specific influences owing to the different kind of metal cations and counter anions, the hydration as well as the different position of the bromine substitution on both the coordination of the complex unit and the network structure of the crystal lattice. The Cu(II) complexes of L1 are five-coordinate [Cu(L1)2NO3]NO3·H2O (1) and [Cu(L1)2Cl]Cl·H2O (2) species with distorted quadratic pyramidal and trigonal bipyramidal coordination geometries of the N2O3 and N2O2Cl donor atoms around the Cu(II), respectively. The Cu(II) complexes of L2 are six-coordinate [Cu(L2)2(NO3)2] (3) and [Cu(L2)2Cl(H2O)]Cl·H2O (4) species with distorted octahedral coordination geometries of the N4O2 and N2O3Cl donor atoms. A distorted octahedral coordination geometry of the N2O2Cl2 donor atoms is also found in the complex unit [Co(L2)2Cl2] of the Co(II) complex 5 but showing the oxygen atoms of the chelating ligand as well as the chloride ions in a cis-position. Depending on the complex, water molecules and chloride anions are shown to act as stabilizing components of the crystal structure. The comparative structural investigation includes also known structures of the bromine-free ligand analogue 2-(hydroxymethyl)pyridine, illustrating the basic implication of the bromine substitution, mostly perceptible in the different modes of crystal packing.
- Hubrich, Michael,Peukert, Max,Seichter, Wilhelm,Weber, Edwin
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body text
p. 1854 - 1862
(2010/07/04)
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- The synthesis of 6-deazaformycin A
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The synthesis of the new C-nucleoside 6-deazaformycin A was achieved through the condensation of a suitably substituted lithiated 2-picoline with 2,3,5-tri-O-benzyl-d-ribonolactone, borohydride reduction of the resulting hemiacetals, followed by intramolecular Mitsunobu cyclization of the carbinols, manipulation of the protecting groups, and subsequent ring closure to result in the formation of 7-amino-3-(β-d-ribofuranosyl)pyrazolo[4,3-b]pyridine. Georg Thieme Verlag Stuttgart.
- Tite, Tony,Lougiakis, Nikolaos,Marakos, Panagiotis,Pouli, Nicole
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scheme or table
p. 2927 - 2930
(2010/02/28)
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- Chiral amine-imine ligands based on trans-2,5-disubstituted pyrrolidines and their application in the palladium-catalyzed allylic alkylation
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A series of amine-imine bidentate ligands based on a trans-2,5-disubstituted pyrrolidine and pyridine moieties have been prepared. The use of these ligands in the palladium-catalyzed allylic alkylation reaction of rac-(E)-1,3-diphenylprop-2-enyl acetate is reported. The results suggest that these ligands are good catalyst precursors for the reaction. Electronic modification on the pyridine ring of the ligands does not have a significant effect on the enantioselectivity of the reaction but does on the reaction rate, while structural modification on either the pyridine or the pyrrolidine moiety affords dramatic changes on the outcome of the stereochemistry. Evidence from various studies suggested that during the palladium-catalyzed allylic alkylation reaction, nucleophilic attack onto the 1,3-diphenylallyl moiety in the transition state occurs mainly trans to the pyridine ring of the less stable conformation of the palladium complexes.
- Chen, Hongfeng,Sweet, James A.,Lam, Kin-Chung,Rheingold, Arnold L.,McGrath, Dominic V.
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scheme or table
p. 1672 - 1682
(2009/12/04)
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- A convenient synthetic route to a useful synthon: 4-bromo-2-pyridinecarboxaldehyde
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We have developed a novel four-step method to synthesise 4-bromo-2-pyridinecarboxaldehyde, from 2-picoline-N-oxide via 4-nitro-2-pyridinecarboxaldehyde, under mild reaction conditions.
- Zaman, Nicolas,Guillot, Régis,Sénéchal-David, Katell,Boillot, Marie-Laure
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body text
p. 7274 - 7275
(2009/04/10)
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- The synthesis of the new C-nucleoside 6-deazaformycin B
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The synthesis of the 6-deaza analogue of formycin B is described, through the condensation of lithiated 4-methoxy-2-methyl-3-trifluoroacetamidopyridine with a suitably protected ribonolactone, dehydration of the resulting hemiacetal, reduction and subsequent ring closure followed by protecting group manipulation. Georg Thieme Verlag Stuttgart.
- Korouli, Stella,Lougiakis, Nikolaos,Marakos, Panagiotis,Pouli, Nicole
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p. 181 - 184
(2008/09/21)
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- Synthesis and antiviral activity evaluation of some novel acyclic C-nucleosides
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The preparation of novel 5-amino or 7-hydroxy substituted pyrazolo[4,3-b]pyridine and pyrazolo[3,4-c]pyridine acyclic C-nucleosides is described. Their synthesis was carried out by condensation of suitably substituted lithiated picolines with 2-benzyloxyethoxymethylchloride followed by pyrazole ring annulation. The compounds were evaluated for their antiviral activity against a wide panel of viruses, but were found inactive at subtoxic concentrations.
- Lougiakis, Nikolaos,Marakos, Panagiotis,Poul, Nicole,Balzarini, Jan
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scheme or table
p. 775 - 780
(2009/06/25)
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- Resonance Raman investigation of equatorial ligand donor effects on the CU2O22+ core in end-on and side-on μ-peroxo-dicopper(II) and bis-μ-oxo-dicopper(III) complexes
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The effect of endogenous donor strength on CU2O2 bonds was studied by electronically perturbing [{(R-TMPA)CuII}2(O2)]2+ and [{(R-MePY2)Cu}2(O2)]2+ (R = H, MeO, Me2N), which form the end-on μ-1,2 bound peroxide and an equilibrium mixture of side-on peroxo- dicopper(II) and bis-μ-oxo-dicopper(III) isomers, respectively. For [{(R-TMPA)CUII}2(O2)]2+, vo-o shifts from 827 to 822 to 812 cm-1 and VCu-O(sym) shifts from 561 to 557 to 551 cm-1, respectively, as R- varies from H to MeO to Me2N. Thus, increasing the N-donor strength to the copper decreases peroxide π*σ donation to the copper, weakening the Cu-O and O-O bonds. A decrease in vCu-O of the bis-μ-oxo- dicopper(III) complex was also observed with increasing N-donor strength for the R-MePY2 ligand system. However, no change was observed for vO-O of the side-on peroxo. This is attributed to a reduced charge donation from the peroxide π*σ orbital with increased N-donor strength, which increases the negative charge on the peroxide and adversely affects the back-bonding from the Cu to the peroxide σ*orbital. However, an increase in the bis-μ-oxo-dicopper(III) isomer relative to side-on peroxo-dicopper(II) species is observed for R-MePY2 with R = H 2N. This effect is attributed to the thermodynamic stabilization of the bis-μ-oxo-dicopper(III) isomer relative to the side-on peroxo-dicopper(II) isomer by strong donor ligands. Thus, the side-on peroxo-dicopper(II)/bis-μ-oxo-dicopper(III) equilibrium can be controlled by electronic as well as steric effects.
- Henson, Mark J.,Vance, Michael A.,Zhang, Christiana Xin,Hong-Chang, Liang,Karlin, Kenneth D.,Solomon, Edward I.
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p. 5186 - 5192
(2007/10/03)
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- N-(phenylsulfonyl)picolinamide derivatives, process for producing the same, and herbicide
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A herbicide containing as the active ingredient an N-(henylsulfonyl)picolinamide derivative represented by general formula (I) wherein X reprcsents a halogeno, a C1-4 alkyl, a C1-4 haloalkyl, a C1-4 alkoxy, a C1-4 haloalkoxy, a (C1-4 alkoxy)carbonyl, a [di(C1-4 alkyl)amino]sulfonyl, an [N—(C1-4 alkyl)-N—(C1-4 alkoxy)amino]sulfonyl, a (C1-4 alkylamino)sulfonyl, a C1-4 alkylthio, a C1-4 alkylsulfinyl, a C1-4 alkylsulfonyl, or nitro; n is an integer of 0 to 5; Y represets a halogeno, a C1-4 alkyl, a C1-4 haloalkyl, a C1-4 alkoxy, C1-4 haloalkoxy, a C1-4 alkylthio, a C1-4 haloalkylthio, amino, a C1-4 alkylamino, a di(C1-4 alkyl)amino, a (C1-4 alkoxy) C1-4 alkyl, a (C1-4 alkylthio) C1-4 alkyl, or nitro; and m is an integer of 0 to 4. This active ingredient is synthesized by condensing a substituted picolinic acid with a substituted benzenesulfonamide under dehydration, or by reacting the phenyl ester of a substituted picolinic acid with a substituted benzenesulfonamide in the presence of a basic compound.
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- Superoxide dismutase activity of iron(II)TPEN complex and its derivatives
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Superoxide is involved in the pathogenesis of various diseases, such as inflammation, ischemia-reperfusion injury and carcinogenesis. Superoxide dismutases (SODs) catalyze the disproportionation reaction of superoxide to produce oxygen and hydrogen peroxide, and can protect living cells against the toxicity of free radicals derived from oxygen. Thus, SODs and their functional mimics have potential value as pharmaceuticals. We have previously reported that Fe(II)tetrakis-N,N,N',N'-(2-pyridylmethyl)ethylenediamine (Fe(II)TPEN) has an excellent SOD activity (IC50=0.5 μM) among many iron complexes examined (J. Biol. Chem., 264, 9243-9249 (1989)). Fe(II)TPEN can act like native SOD in living cells, and protect Escherichia coli cells from free radical toxicity caused by paraquat. In order to develop more effective SOD functional mimics, we synthesized Fe(II)TPEN derivatives with electron-donating or electron-withdrawing groups at the 4-position of all pyridines of TPEN, and measured the SOD activities and the redox potentials of these complexes. Fe(II) tetrakis-N,N,N',N'-(4-methoxy-2-pyridylmethyl)ethylenediamine (Fe(II)(4MeO)4TPEN) had the highest SOD activity (IC50=0.1 μM) among these iron-based SOD mimics. In addition, a good correlation was found between the redox potential and the SOD activity of 15 Fe(II) complexes, including iron-based SOD mimics reported in the previous paper (J. Organometal. Chem., in press). Iron-based SOD mimics may be clinically applicable, because these complexes are generally tissue-permeable and show low toxicity. Therefore our findings should be significant for the development of clinically useful SOD mimics.
- Tamura,Urano,Kikuchi,Higuchi,Hirobe,Nagano
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p. 1514 - 1518
(2007/10/03)
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- Carbonylation of hydrocarbylpalladium(II) complexes containing substituted pyridinecarboxylate chelating ligands. Steric and electronic manipulation of the CO-insertion mechanism
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Organopalladium(II) complexes of general formula [PdR(N-O)L] [R = Ph, N-O = pyridinecarboxylate (pyca), L = P(C6H11)3; R = Ph, N-O = 6-methylpyridinecarboxylate (mpyca), L = PPh3, PMePh2, P(C6H11)3 or PEt3; R = Ph, N-O = 4-nitropyridinecarboxylate (npyca), L = P(C6H11)3; R = Ph, N-O = 6-methyl-4-nitropyridinecarboxylate, L = P(C6H11)3; R = Me, N-O = mpyca, L = PPh3, P(CH2Ph)3 or P(C6H11)3; R = Me, N-O = npyca, L = PPh3, PMePh2 or P(C6H11)3] have been prepared, and their carbonylation reactions studied in detail. Kinetic studies of the CO-insertion process have indicated that the rate of reaction decreases as the basicity of the phosphine, L, increases. Complexes containing the highly basic phosphine P(C6H11)3 only undergo carbonylation if hemilability of the chelating ligand is promoted (by substitution of the N-O chelate). Substitution of the N-O ligand modifies the carbonylation pathway and provides an alternative route from that generally observed for palladium(II) and platinum(II) hydrocarbyl complexes of pyca. A mechanism for insertion of CO involving partial dissociation of the N-O chelate is proposed for these complexes. The crystal stucture of [PdMe(mpyca)(PPh3)] has been determined. The complex has square-planar co-ordination with the nitrogen of pyca trans to the phosphorus. Considerable distortion of the inner co-ordination sphere is evident, caused by steric interactions betwen the σ-methyl ligand and the methyl group on the N-O ligand.
- Hoare, Jason L.,Cavell, Kingsley J.,Hecker, Richard,Skelton, Brian W.,White, Allan H.
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p. 2197 - 2205
(2007/10/03)
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- Heterodimeric bis(amino thiol) complexes of oxorhenium(V) that mimic the structure of steroid hormones. Synthesis and stereochemical issues
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We have prepared a series of bis-bidentate complexes of rhenium that mimic the size, shape, and peripheral functionality of steroidal androgens. In a model system, we used 2D NMR and X-ray crystallographic analysis to show that adjacent N-methyl and oxo substitutents adopt an anti configuration during the coordination reaction. We have synthesized a bis-bidentate oxorhenium(V) complex whose structure and peripheral functionality mimic 5α-dihydrotestosterone. 2D-NMR analysis indicates that the N-methyl and oxo substituents are driven into the steroidal anti configuration (β-N-methyl, α-oxo) by the β-orientation of the methyl group equivalent to C-18. Thus, this metal complex provides a remarkable structural and stereochemical mimic of a steroid. Its in vivo stability, however, appears to be limited.
- Hom, Roy K.,Chi, Dae Yoon,Katzenellenbogen, John A.
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p. 2624 - 2631
(2007/10/03)
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- Structure-activity relationship of omeprazole and analogues as Helicobacter pylori urease inhibitors
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Helicobacter pylori urease belongs to a family of highly conserved urea- hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and a reactive cysteine residue in the active site. The H+/K+-ATPase inhibitor omeprazole is a prodrug of a sulfenamide which covalently modifies cysteine residues on the luminal side of the H+/K+- ATPase of gastric parietal cells. Omeprazole and eight analogues were selected based on their chemical, electronic, and kinetic properties, and each was incubated with viable H. pylori in phosphate-buffered saline at pH 7.4 for 30 min, after which 100 mM urea was added and the amount of ammonia formed analyzed after a further 10 min. Inhibition between 0% and 100% at a 0.1 mM concentration was observed for the different analogues and could be expressed as a function of the pK(a)-value of the pyridine, the pK(a)-value of the benzimidazole, the overall lipophilicity, and, most importantly, the rate of sulfenamide formation, in a quantitative structure-activity relationship. The inhibition was potentiated by a lower pH (favoring the formation of the sulfenamide) but abolished in the presence of β- mercaptoethanol (a scavenger of the sulfenamide). Structural analogues incapable of yielding the sulfenamide did not inhibit ammonia production. Treatment of Helicobacter felis-infected mice with 230 μmol/kg flurofamide b.i.d. for 4 weeks, known to potently inhibit urease activity in vivo, as a means of eradicating the infection, was tested and compared with the effect of 125 μmol/kg omeprazole b.i.d. for 4 weeks. Neither treatment proved efficacious.
- Kuhler,Fryklund,Bergman,Weilitz,Lee,Larsson
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p. 4906 - 4916
(2007/10/03)
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- 5-SUBSTITUTED IMIDAZO[4,5-C]PYRIDINES
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The present invention relates to a class of compounds represented by the formula STR1 or a pharmaceutically acceptable salt thereof useful in the treatment of diseases or disorders mediated by platelet activating factor (PAF).
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- (H+,K+)-ATPase inhibiting 2-[(2-pyridylmethyl)sulfinyl]benzimidazoles. 4. A novel series of dimethoxypyridyl-substituted inhibitors with enhanced selectivity. The selection of pantoprazole as a clinical candidate
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[(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the nonselective thiophile 4 solely at low pH, thus avoiding interaction with other thiol groups in the body. The propensity to undergo the acid-catalyzed transformation is dependent on the nucleophilic/electrophilic properties of the functional groups involved in the formation of 2 since this step is both rate-determining and pH-dependent. The aim of this study was to identify compounds with high (H+,K+)-ATPase inhibitory activity in stimulated gastric glands possessing acidic pH, but low reactivity (high chemical stability) at neutral pH as reflected by in vitro (Na+,K+)-ATPase inhibitory activity. The critical influence of substituents flanking the pyridine 4-methoxy substituent present in all derivatives was carefully studied. The introduction of a 3-methoxy group gave inhibitors possessing a combination of high potency, similar to omeprazole and lansoprazole, but increased stability. As a result of these studies, compound 1a (INN pantoprazole) was selected as a candidate drug and is currently undergoing phase III clinical studies.
- Kohl,Sturm,Senn-Bilfinger,Simon,Kruger,Schaefer,Rainer,Figala,Klemm
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p. 1049 - 1057
(2007/10/02)
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- Substituted thienoimidazole derivatives, pharmaceutical compositions containing them, and their use as inhibitors of gastric acid secretion
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The invention relates to compounds of the formula STR1 in which A represents STR2 T denotes --S--, --SO-- or --SO2 --, and R1 to R9 have the meanings given in the description, to a process for their preparation, to pharmaceutical compositions containing them, and to their use as inhibitors of gastric acid secretion.
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