共查询到20条相似文献,搜索用时 31 毫秒
1.
Hanessian S Larsson A Fex T Knecht W Blomberg N 《Bioorganic & medicinal chemistry letters》2010,20(23):6925-6928
The synthesis of a series of novel macrocyclic compounds designed to target blood coagulation Factor XIa is described. The compounds were evaluated for their inhibition of a small set of serine proteases. Several compounds displayed modest activity and good selectivity for Factor XIa. Within the series, a promising lead structure for developing novel macrocyclic inhibitors of thrombin was identified. 相似文献
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3.
A. Kaars Sijpesteijn F. Rijkens J. G. A. Luijten L. C. Willemsens 《Antonie van Leeuwenhoek》1962,28(1):346-356
Summary The antifungal and antibacterial activities of a number of acetates of trialkyl- and triphenyl-substituted germanium, tin
and lead have been investigated. All three groups contain active as well as inactive compounds. High activity was found for
certain tin and lead compounds, whereas activity of the germanium compounds was much lower.
The activity optimum in the three trialkyl series varied according to the nature of the central atom and the type of organism
used. A possible reason for these differences and a probable mode of action of the compounds are discussed. 相似文献
4.
Alan Brown David Ellis David A. Favor Tony Kirkup Wolfgang Klute Malcolm MacKenny Gordon McMurray Adam Stennett 《Bioorganic & medicinal chemistry letters》2013,23(22):6118-6122
A new series of 2-(benzyloxy)benzamides are presented that are potent functional antagonists of TRPM8 and possess improved LipE and LE compared to the original lead. They were discovered through a series of compound libraries and we present a powerful visualization method for the chemical space explored with each library. Remarkably this new series originated from the highest risk design strategy where compounds were synthesised with the least degree of similarity to the lead structure. 相似文献
5.
On the basis of the structure of (R)-rosmarinic acid, a series of small chemical compounds with a different scaffold was synthesized as inhibitors for lck SH2 domain. From ELISA results, most of all chemical compounds showed a similar or a little lower binding activity for lck SH2 domain compared to the lead compound, (R)-rosmarinic acid. It was characterized that the backbone rigidity between two catechol substructures was required for the full activity and acid substructure of the lead compound was important for the activity. We successfully identified novel lead compounds that did not contain phosphotyrosine moiety and might have an improved bioavailability as inhibitor for lck SH2 domain. 相似文献
6.
Morisseau C Newman JW Tsai HJ Baecker PA Hammock BD 《Bioorganic & medicinal chemistry letters》2006,16(20):5439-5444
We prepared a series of amino acid derived cyclohexyl and adamantyl ureas and tested them as inhibitors of the human soluble epoxide hydrolase, and obtained very potent compounds (K(I)=15nM) that are >10-fold more soluble than previously described sEH inhibitors. While our lead compound 2 showed low apparent bioavailability in dogs and rats, this series of compounds revealed that sEH inhibitor structures could accept large groups that could lead to better orally available drugs. 相似文献
7.
Chen MH Fitzgerald P Singh SB O'Neill EA Schwartz CD Thompson CM O'Keefe SJ Zaller DM Doherty JB 《Bioorganic & medicinal chemistry letters》2008,18(6):2222-2226
Synthesis and biological activities of some quinolinone and dihydroquinolinone p38 MAP kinase inhibitors are reported. Modifications to the dihydroquinolinone pharmacophore revealed that dihydroquinolinone may be replaced with a quinolinone pharmacophore and lead to enhanced p38 inhibitory activity. From a study of C-7 substitutions by amino acid side chains, a very potent series of compounds in the p38 enzyme assays was identified. Translation of the in vitro activity into reasonable whole blood activity can be improved in this series of compounds by judicious modification of the physical properties at appropriate regions of the lead. 相似文献
8.
Masood MA Selby MD Bell AS Mansfield AC Gardner M Smith GF Lane C Kenyon-Edwards H Osborne R Jones RM Liu WL Brown CD Clarke N Perrucio F Mowbray CE 《Bioorganic & medicinal chemistry letters》2011,21(21):6591-6595
We describe the identification of a potent, selective lead series that shows antagonism against the human histamine H4 receptor from thirteen actives identified in an HTS as part of a hit to lead program. By focusing on ligand efficiency and concurrently using a diversity based approach, compounds based around 2,4-diaminopyrimidine were identified with compound 25 being quickly shown to be a good lead. It also had the highest ligand efficiency in the series. 相似文献
9.
Yuanchao Xie Bing Huang Kexiang Yu Wenfang Xu 《Bioorganic & medicinal chemistry》2013,21(24):7715-7723
Eight series of compounds, each series containing two to five compounds were prepared by structural modifications of a lead, which was previously discovered as a mild influenza neuraminidase (NA) inhibitor. On the basis of the biological result, a detailed structure–activity relationship (SAR) was derived and discussed. Several caffeic acid derivatives that acted as non-competitive inhibitors were close or superior to the lead and also presented good antiviral activities in cells. Besides, it was interesting to find that modifications of the lead with different strategies could result in selective inhibition against N1 or N2. The preliminary docking analysis indicated that the 150-cavity of the enzymes played an important role in the selective inhibition. 相似文献
10.
Hayes ME Breinlinger EC Wallace GA Grongsaard P Miao W McPherson MJ Stoffel RH Green DW Roth GP 《Bioorganic & medicinal chemistry letters》2008,18(7):2414-2419
Modification of a 2-iminobenzimidazole series derived from an HTS hit resulted in compounds with improved in-vitro species selectivity. Incorporation of an 8-quinoline amide and conformational rigidification of an aliphatic tether furnished potent compounds suitable for further lead optimization. 相似文献
11.
Zheng X Hodgetts KJ Brielmann H Hutchison A Burkamp F Brian Jones A Blurton P Clarkson R Chandrasekhar J Bakthavatchalam R De Lombaert S Crandall M Cortright D Blum CA 《Bioorganic & medicinal chemistry letters》2006,16(19):5217-5221
Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series. 相似文献
12.
Clark RF Zhang T Xin Z Liu G Wang Y Hansen TM Wang X Wang R Zhang X Frevert EU Camp HS Beutel BA Sham HL Gu YG 《Bioorganic & medicinal chemistry letters》2006,16(23):6078-6081
Structure-activity relationships for a recently discovered thiazolyl phenyl ether series of acetyl-CoA carboxylase (ACC) inhibitors were investigated. Preliminary efforts to optimize the series through modification of the distal aryl ether moiety of the lead scaffold resulted in the identification of compounds exhibiting low-nanomolar potency and isozyme-selective ACC2 activity. 相似文献
13.
René Csuk Alexander Barthel Ralph Kluge Dieter Ströhl Harish Kommera Reinhard Paschke 《Bioorganic & medicinal chemistry》2010,18(3):1344-1355
The reaction of betulinic aldehydes with various carbon nucleophiles gave a series of new betulin derivatives, among them epoxides, glycidic derivatives and β-hydroxy carbonyl compounds. Subsequent transformations of the β-hydroxy carbonyls lead to 1,3-diketo- and α,β-unsaturated betulin derivatives. These compounds were assayed for cytotoxicity using 15 human cancer cell lines and a colorimetric SRB-assay. Several compounds revealed significant antitumour activity. 相似文献
14.
Rando DG Sato DN Siqueira L Malvezzi A Leite CQ do Amaral AT Ferreira EI Tavares LC 《Bioorganic & medicinal chemistry》2002,10(3):557-560
Nitroaromatic compounds such as nifuroxazide are used in many human enteropathogenic bacteria infections without causing an increase in the plasmidial antibiotic resistance of the aerobic Gram-negative intestinal Enterobacteriaceae. For these reasons, these compounds have been synthesized using the rational approach of Topliss' decision tree. Generally, this approach allows us to obtain the most active derivative from the series in a few steps. These compounds were tested against Mycobacterium tuberculosis in vitro and the most active of the series identified. A new lead for potential tuberculostatic activity has been predicted and will be used in further QSAR studies. 相似文献
15.
Ureas of 5-aminopyrazole and 2-aminothiazole inhibit growth of gram-positive bacteria 总被引:1,自引:0,他引:1
Kane JL Hirth BH Liang B Gourlie BB Nahill S Barsomian G 《Bioorganic & medicinal chemistry letters》2003,13(24):4463-4466
Ureas of 5-aminopyrazole and 2-aminothiazole emerged as lead compounds from a high-throughput screen assaying the growth of Staphylococcus aureus. Structure–activity relationships were developed for each compound series. Several compounds were also tested for activity against drug resistant strains of S. aureus in vivo. 相似文献
16.
Stavitskaya L Shim J Healy JR Matsumoto RR MacKerell AD Coop A 《Bioorganic & medicinal chemistry》2012,20(14):4556-4563
A series of phenylpropyloxyethylamines and cinnamyloxyethylamines were synthesized as deconstructed analogs of 14-phenylpropyloxymetopon and analyzed for opioid receptor binding affinity. Using the Conformationally Sampled Pharmacophore modeling approach, we discovered a series of compounds lacking a tyrosine mimetic, historically considered essential for μ opioid binding. Based on the binding studies, we have identified the optimal analogs to be N-methyl-N-phenylpropyl-2-(3-phenylpropoxy)ethanamine, with 1520 nM, and 2-(cinnamyloxy)-N-methyl-N-phenethylethanamine with 1680 nM affinity for the μ opioid receptor. These partial opioid structure analogs will serve as the novel lead compounds for future optimization studies. 相似文献
17.
Lesuisse D Mauger J Nemecek C Maignan S Boiziau J Harlow G Hittinger A Ruf S Strobel H Nair A Ritter K Malleron JL Dagallier A El-Ahmad Y Guilloteau JP Guizani H Bouchard H Venot C 《Bioorganic & medicinal chemistry letters》2011,21(8):2224-2228
A new series of IGF-1R inhibitors related to hydantoins were identified from a lead originating from HTS. Their noncompetitive property as well as their slow binding characteristics provided a series of compounds with unique selectivity and excellent cellular activities. 相似文献
18.
Eastwood P González J Gómez E Caturla F Balagué C Orellana A Domínguez M 《Bioorganic & medicinal chemistry letters》2011,21(18):5270-5273
Optimisation of a series of indolin-2-one p38α inhibitors was achieved via both blocking of a potential metabolic 'hot spot' and by increasing overall polarity of the lead series leading to non-cytotoxic compounds which showed improved oral bioavailabilities in the rat. 相似文献
19.
Hudson AR Higuchi RI Roach SL Valdez LJ Adams ME Vassar A Rungta D Syka PM Mais DE Marschke KB Zhi L 《Bioorganic & medicinal chemistry letters》2011,21(6):1654-1657
Continuing studies based on dihydroquinoline glucocorticoid receptor agonists lead to the discovery of a series of C4-oxime analogs. Representative compounds exhibited potent transrepression activity with minimal transactivation of phosphoenolpyruvate caboxykinase (PEPCK), a key protein in the gluconeogenesis pathway. These compounds represent promising leads in identifying GR agonists with high anti-inflammatory activity and attenuated potential for glucose elevation. 相似文献
20.
Kamal A Khan MN Srikanth YV Reddy KS Juvekar A Sen S Kurian N Zingde S 《Bioorganic & medicinal chemistry》2008,16(16):7804-7810
A series of triazolobenzothiadiazine-pyrrolobenzodiazepine conjugates linked through different alkane spacers have been prepared. These compounds have exhibited significant cytotoxicity against most of the cell lines examined. Compound 5a displays GI(50) values from 1.83 to 2.38 microM against seven human tumour cell lines, and is identified as a promising lead compound from this series. Their DNA thermal denaturation studies have also been carried out, and one of the compounds 5c elevates the DNA helix melting temperature of the CT-DNA by 2.6 degrees C after incubation for 36 h. 相似文献