共查询到20条相似文献,搜索用时 0 毫秒
1.
Jack D. Scott Michael W. Miller Sarah W. Li Sue-Ing Lin Henry A. Vaccaro Liwu Hong Deborra E. Mullins Mario Guzzi Jay Weinstein Robert A. Hodgson Geoffrey B. Varty Andrew W. Stamford Tin-Yau Chan Brian A. McKittrick William J. Greenlee Tony Priestley Eric M. Parker 《Bioorganic & medicinal chemistry letters》2009,19(21):6018-6022
Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors. 相似文献
2.
Chen YL Cherry K Corman ML Ebbinghaus CF Gamlath CB Liston D Martin BA Oborski CE Sahagan BG 《Bioorganic & medicinal chemistry letters》2007,17(20):5518-5522
The thiazole-diamide series (1) has been identified as highly potent gamma-secretase inhibitors. Several representative compounds showed IC(50) values of <0.3 nM. The synthesis and SAR, as well as a radiolabeled synthesis of [(3)H]-2a, are described. 相似文献
3.
Parker MF Bronson JJ Barten DM Corsa JA Du W Felsenstein KM Guss VL Izzarelli D Loo A McElhone KE Marcin LR Padmanabha R Pak R Polson CT Toyn JH Varma S Wang J Wong V Zheng M Roberts SB 《Bioorganic & medicinal chemistry letters》2007,17(21):5790-5795
A series of amino-caprolactam sulfonamides were developed from a screening hit. Compounds with good in vitro and in vivo gamma-secretase activity are reported. 相似文献
4.
Prasad CV Wallace OB Noonan JW Sloan CP Lau W Vig S Parker MF Smith DW Hansel SB Polson CT Barten DM Felsenstein KM Roberts SB 《Bioorganic & medicinal chemistry letters》2004,14(8):1917-1921
Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM. 相似文献
5.
Bergstrom CP Sloan CP Lau WY Smith DW Zheng M Hansel SB Polson CT Corsa JA Barten DM Felsenstein KM Roberts SB 《Bioorganic & medicinal chemistry letters》2008,18(2):464-468
The synthesis and gamma-secretase inhibition data for a series of carbamate-appended N-alkylsulfonamides are described. Carbamate 54 was found to significantly reduce brain Abeta in transgenic mice. 54 was also found to possess markedly improved brain levels in transgenic mice compared to previously disclosed 1 and 2. 相似文献
6.
Bergstrom CP Sloan CP Wang HH Parker MF Smith DW Zheng M Hansel SB Polson CT Barber LE Bursuker I Guss VL Corsa JA Barten DM Felsenstein KM Roberts SB 《Bioorganic & medicinal chemistry letters》2008,18(1):175-178
The synthesis and gamma-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11-47) are described. Inhibition of brain Abeta in transgenic mice was demonstrated by two of these compounds (23 and 44). 相似文献
7.
Pissarnitski DA Asberom T Bara TA Buevich AV Clader JW Greenlee WJ Guzik HS Josien HB Li W McEwan M McKittrick BA Nechuta TL Parker EM Sinning L Smith EM Song L Vaccaro HA Voigt JH Zhang L Zhang Q Zhao Z 《Bioorganic & medicinal chemistry letters》2007,17(1):57-62
A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned. 相似文献
8.
Shaw D Best J Dinnell K Nadin A Shearman M Pattison C Peachey J Reilly M Williams B Wrigley J Harrison T 《Bioorganic & medicinal chemistry letters》2006,16(11):3073-3077
The 3,4-fused sulfamides, sulfonamides and sulfone have been identified as highly potent gamma-secretase inhibitors. Evaluation of the SAR of substitution within these series has allowed the identification of a range of compounds which significantly reduce brain A beta in transgenic mouse models and thus have potential as possible treatments for Alzheimer's disease. 相似文献
9.
Ya-Sheng Li Xing-Yu Liu Dong-Sheng Zhao Yi-Xian Liao Lian-Hui Zhang Feng-Zhi Zhang Gao-Peng Song Zi-Ning Cui 《Bioorganic & medicinal chemistry letters》2018,28(19):3271-3275
Tetrahydroquinoline and tetrahydroisoquinoline derivatives containing 2-phenyl-5-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds showed good inhibitory activity against PDE4B and blockade of LPS (lipopolysaccharide) induced TNF-α release, which also exhibited considerable in vivo activity in animal models of asthma/COPD (chronic obstructive pulmonary disease) and sepsis induced by LPS. The bioactivity of compounds containing tetrahydroquinoline (series 4) was higher than that of tetrahydroisoquinoline derivatives (series 3). Compound 4?m with 4-methoxybenzene moiety exhibited the best potential selective activity against PDE4B. The primary structure–activity relationship study and docking results showed that the tetrahydroquinoline moiety of compound 4?m played a key role to form hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Based on LPS induced sepsis model for the measurement of TNF-α inhibition in Swiss Albino mice and neutrophilia inhibition for asthma and COPD in Sprague Dawley rats with the potential molecules, compound 4?m would be great promise as a hit inhibitor in the future study. 相似文献
10.
Mustafa G Khan IU Ashraf M Afzal I Shahzad SA Shafiq M 《Bioorganic & medicinal chemistry》2012,20(8):2535-2539
The present study describes a convenient method for the synthesis of new lipoxygenase inhibitors, 4-(toluene-4-sulfonylamino)-benzoic acids from p-amino benzoic acid. Reaction of p-amino benzoic acid with p-toluenesulfonyl chloride provided thirteen N- and O-alkylation products 4a-4m in moderate to good yields. Lipoxygenase inhibition of newly formed sulfonamide derivatives was investigated and some of these compounds 4m, 4g, 4e, 4f and 4j showed good lipoxygenase inhibitory activities with IC(50) values ranged between 15.8 ± 0.57 and 91.7 ± 0.61 μmol whilst all other compounds exhibited mild anti-lipoxygenase activities with IC(50) values ranged between 139.2 ± 0.75 and 232.1 ± 0.78 μmol. N-alkylated products were more active against the enzyme than O-alkylated or both N- and O-alkylated ones. All synthesized sulfonamides were recrystallized in chloroform to give these title compounds which were characterized using FTIR, (1)H NMR, (13)C NMR, elemental analysis and single crystal X-ray diffraction techniques. 相似文献
11.
Li H Asberom T Bara TA Clader JW Greenlee WJ Josien HB McBriar MD Nomeir A Pissarnitski DA Rajagopalan M Xu R Zhao Z Song L Zhang L 《Bioorganic & medicinal chemistry letters》2007,17(22):6290-6294
Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. 相似文献
12.
Prasad CV Vig S Smith DW Gao Q Polson CT Corsa JA Guss VL Loo A Barten DM Zheng M Felsenstein KM Roberts SB 《Bioorganic & medicinal chemistry letters》2004,14(13):3535-3538
2,3-Benzodiazepin-1,4-diones were designed as peptidomimetics at the carboxy terminus of hydroxyamides. Inhibition of brain Abeta production was improved by one of the compounds containing constrained modification. 相似文献
13.
M. Alexandra Esteves Osvaldo Ortet Anabela Capelo Claudiu T. Supuran Sérgio M. Marques M. Amélia Santos 《Bioorganic & medicinal chemistry letters》2010,20(12):3623-3627
A set of benzenesulfonamide (BSA) derivatives bearing a hydroxypyrimidinone (HPM) moiety were synthesized and investigated for their inhibitory activity against several carbonic anhydrase (CA, EC 4.2.1.1) isozymes. They all revealed to be very potent inhibitors (nanomolar order) of the cytosolic CA I and II isozymes, but especially of the transmembrane, tumor-associated CA IX isozyme, a beneficial feature for a potential antitumor effect of these compounds. Further structure optimization aimed at improving the specificity of CA inhibition and enhancing their matrix metalloproteinase (MMP) inhibitory activity may also lead to new compounds with an attractive dual mechanism of action as antitumor agents. 相似文献
14.
Sparey T Beher D Best J Biba M Castro JL Clarke E Hannam J Harrison T Lewis H Madin A Shearman M Sohal B Tsou N Welch C Wrigley J 《Bioorganic & medicinal chemistry letters》2005,15(19):4212-4216
A novel series of N-alkyl-substituted cyclic sulfamides were developed from a screening hit. Chemistries were developed which allowed surveys of N-alkyl groups and amines resulting in the identification of N-trifluoroethyl-substituted cyclic sulfamides with good in vitro and in vivo gamma-secretase activity. One compound with subnanomolar activity elicited a reduction in brain Abeta40 after oral dosing in APP-YAC mice. 相似文献
15.
Ekinci D Al-Rashida M Abbas G Şentürk M Supuran CT 《Journal of enzyme inhibition and medicinal chemistry》2012,27(5):744-747
A series of sulfonamide derivatives incorporating substituted 3-formylchromone moieties were investigated for the inhibition of three human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, and VI. All these compounds, together with the clinically used sulfonamide acetazolamide, were investigated as inhibitors of the physiologically relevant isozymes I, II (cytosolic), and VI (secreted isoform). These sulfonamides showed effective inhibition against all these isoforms with K(I)'s in the range of 0.228 to 118 μM. Such molecules can be used as leads for discovery of novel effective CA inhibitors against other isoforms with medicinal chemistry applications. 相似文献
16.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):744-747
A series of sulfonamide derivatives incorporating substituted 3-formylchromone moieties were investigated for the inhibition of three human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, and VI. All these compounds, together with the clinically used sulfonamide acetazolamide, were investigated as inhibitors of the physiologically relevant isozymes I, II (cytosolic), and VI (secreted isoform). These sulfonamides showed effective inhibition against all these isoforms with KI’s in the range of 0.228 to 118 µM. Such molecules can be used as leads for discovery of novel effective CA inhibitors against other isoforms with medicinal chemistry applications. 相似文献
17.
Josien H Bara T Rajagopalan M Asberom T Clader JW Favreau L Greenlee WJ Hyde LA Nomeir AA Parker EM Pissarnitski DA Song L Wong GT Zhang L Zhang Q Zhao Z 《Bioorganic & medicinal chemistry letters》2007,17(19):5330-5335
The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease. 相似文献
18.
Ravi Keerti A Ashok Kumar B Parthasarathy T Uma V 《Bioorganic & medicinal chemistry》2005,13(5):1873-1878
A series of benzodiazepine compounds, which act as gamma-secretrase inhibitors were subjected to QSAR studies. A correlation between the physicochemical properties QlogP, SMR and the inhibitory activity was obtained and a model equation was generated to predict the best possible pharmacophore for treating Alzheimer's disease. The inhibitory activity of the compound depends on the lipophilicity positively and is sensitive to small changes in its SMR. The compound with a high lipophilicity (around 9.31) and low SMR gives a potent activity. 相似文献
19.
Stranix BR Sauvé G Bouzide A Coté A Sévigny G Yelle J Perron V 《Bioorganic & medicinal chemistry letters》2004,14(15):3971-3974
A series of lysine sulfonamide analogues bearing a Nepsilon-benzylic ureas was synthesized using both solution-phase and solid-phase approaches. A novel synthetic route of Nalpha-(alkyl)-Nalpha-(sulfonamides)lysinol using alpha-amino-caprolactam was developed. Evaluation of these novel protease inhibitors revealed compounds with high potency against wild-type HIV virus. 相似文献
20.
Churcher I Beher D Best JD Castro JL Clarke EE Gentry A Harrison T Hitzel L Kay E Kerrad S Lewis HD Morentin-Gutierrez P Mortishire-Smith R Oakley PJ Reilly M Shaw DE Shearman MS Teall MR Williams S Wrigley JD 《Bioorganic & medicinal chemistry letters》2006,16(2):280-284
The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice). 相似文献