共查询到20条相似文献,搜索用时 31 毫秒
1.
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
2.
《Bioorganic & medicinal chemistry letters》2020,30(21):127502
A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment. 相似文献
3.
Synthesis and evaluation of 3-anilino-quinoxalinones as glycogen phosphorylase inhibitors 总被引:1,自引:0,他引:1
Dudash J Zhang Y Moore JB Look R Liang Y Beavers MP Conway BR Rybczynski PJ Demarest KT 《Bioorganic & medicinal chemistry letters》2005,15(21):4790-4793
A series of 3-anilino-quinoxalinones has been identified as a new class of glycogen phosphorylase inhibitors. The lead compound 1 was identified through high throughput screening as well as through pharmacophore-based electronic screening. Modifications were made to the scaffold of 1 to produce novel analogues, some of which are 25 times more potent than the lead compound. 相似文献
4.
Lippa B Pan G Corbett M Li C Kauffman GS Pandit J Robinson S Wei L Kozina E Marr ES Borzillo G Knauth E Barbacci-Tobin EG Vincent P Troutman M Baker D Rajamohan F Kakar S Clark T Morris J 《Bioorganic & medicinal chemistry letters》2008,18(11):3359-3363
Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po). 相似文献
5.
《Bioorganic & medicinal chemistry》2016,24(13):2954-2963
Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, Log D, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency. 相似文献
6.
Torisu K Kobayashi K Iwahashi M Egashira H Nakai Y Okada Y Nanbu F Ohuchida S Nakai H Toda M 《Bioorganic & medicinal chemistry letters》2004,14(17):4557-4562
A series of Indomethacin analogs were synthesized and biologically evaluated. Among the compounds tested, N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid 2 was discovered as a new chemical lead for a prostaglandin D2 (PGD2) receptor antagonist. Structure-activity relationship data are also presented. 相似文献
7.
Fabien Hammerer Florent Poyer Laura Fourmois Su Chen Guillaume Garcia Marie-Paule Teulade-Fichou Philippe Maillard Florence Mahuteau-Betzer 《Bioorganic & medicinal chemistry》2018,26(1):107-118
The proof of concept for two-photon activated photodynamic therapy has already been achieved for cancer treatment but the efficiency of this approach still heavily relies on the availability of photosensitizers combining high two-photon absorption and biocompatibility. In this line we recently reported on a series of porphyrin-triphenylamine hybrids which exhibit high singlet oxygen production quantum yield as well as high two-photon absorption cross-sections but with a very poor cellular internalization. We present herein new photosensitizers of the same porphyrin-triphenylamine hybrid series but bearing cationic charges which led to strongly enhanced water solubility and thus cellular penetration. In addition the new compounds have been found localized in mitochondria that are preferential target organelles for photodynamic therapy. Altogether the strongly improved properties of the new series combined with their specific mitochondrial localization lead to a significantly enhanced two-photon activated photodynamic therapy efficiency. 相似文献
8.
Gharbaoui T Skinner PJ Shin YJ Averbuj C Jung JK Johnson BR Duong T Decaire M Uy J Cherrier MC Webb PJ Tamura SY Zou N Rodriguez N Boatman PD Sage CR Lindstrom A Xu J Schrader TO Smith BM Chen R Richman JG Connolly DT Colletti SL Tata JR Semple G 《Bioorganic & medicinal chemistry letters》2007,17(17):4914-4919
A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization. 相似文献
9.
Clare BW Scozzafava A Briganti F Iorga B Supuran CT 《Journal of enzyme inhibition》2000,15(3):235-264
Two series of derivatives have been prepared and assayed as inhibitors of two physiologically relevant serine proteases, human thrombin and human trypsin. The first series includes alkyl-/ aralkyl-/aryl- and hetarylsulfonyl-aminoguanidines. It was thus observed that sulfanilyl-aminoguanidine possesses moderate but intrinsically selective thrombin inhibitory properties, with KI values around 90 and 1400 nM against thrombin and trypsin respectively. Further elaboration of this molecule afforded compounds that inhibited thrombin with KI values in the range 10-50 nM, whereas affinity for trypsin remained relatively low. Such compounds were obtained either by attaching benzyloxycarbonyl- or 4-toluenesulfonylureido-protected amino acids (such as D-Phe, L-Pro) or dipeptides (such as Phe-Pro, Gly His, beta-Ala-His or Pro-Gly) to the N-4 atom of the lead molecule, sulfanilyl-aminoguanidine, or by attaching substituted-pyridinium propylcarboxamido moieties to this lead. Thus, this study brings novel insights regarding a novel non-basic S1 anchoring moiety (i.e., SO2NHNHC(=NH)NH2), and new types of peptidomimetic scaffolds obtained by incorporating tosylureido-amino acids/pyridinium-substituted-GABA moieties in the hydrophobic binding site(s). Structure-activity correlations of the new serine protease inhibitors are also discussed based on a QSAR model described previously for a large series of structurally-related derivatives (Supuran et al. (1999) J. Med. Chem., in press). 相似文献
10.
Michaux C Rolin S Dogné JM Durant F Masereel B Delarge J Wouters J 《Bioorganic & medicinal chemistry letters》2001,11(8):1019-1022
BM567, a sulfonylurea compound whose crystal structure is here discussed and terbogrel, are both thromboxane receptor antagonists and thromboxane synthase inhibitors. In this paper, their crystallographic and electronic structures are compared and lead to new synthesis prospects among the sulfonylurea series. 相似文献
11.
Tasler S Kraus J Wuzik A Müller O Aschenbrenner A Cubero E Pascual R Quintana-Ruiz JR Dordal A Mercè R Codony X 《Bioorganic & medicinal chemistry letters》2007,17(22):6224-6229
Based on a pharmacophore alignment on a 5-HT(6) ligand applying 4SCan technology, a new lead series was identified and further structurally investigated. K(i)s down to 8 nM were achieved. 相似文献
12.
Shyh-Ming Yang Daniel J. Urban Makoto Yoshioka Jeffrey W. Strovel Steven Fletcher Amy Q. Wang Xin Xu Pranav Shah Xin Hu Matthew D. Hall Ajit Jadhav David J. Maloney 《Bioorganic & medicinal chemistry letters》2018,28(21):3483-3488
A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization. 相似文献
13.
Glória PM Gut J Gonçalves LM Rosenthal PJ Moreira R Santos MM 《Bioorganic & medicinal chemistry》2011,19(24):7635-7642
A series of novel aza vinyl sulfones were designed, synthesized in good yields and evaluated as antiplasmodial agents. Tested compounds did not show activity against papain or the Plasmodium falciparum cysteine protease falcipain-2. However, a number of the new compounds effectively inhibited the in vitro development of P. falciparum. Compounds containing a squaramide group were the most active, with IC50 values between 0.95 and 4.5 μM, suggesting that these are potential lead compounds for the development of new antimalarial agents. 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.
《Bioorganic & medicinal chemistry letters》2020,30(16):127298
We report on the discovery of the new clinical candidate BAY 1003803 as glucocorticoid receptor agonist for the topical treatment of psoriasis or severe atopic dermatitis. In the course of optimizing the amino alcohol series as a highly potent new non-steroidal lead structure, considerations were made as to how physicochemical properties and safety concerns relate to structural motifs. BAY 1003803 demonstrates strong anti-inflammatory activity in vitro paired with a pharmacokinetic profile suitable for topical application. 相似文献
16.
Tasler S Kraus J Pegoraro S Aschenbrenner A Poggesi E Testa R Motta G Leonardi A 《Bioorganic & medicinal chemistry letters》2005,15(11):2876-2880
Based on a pharmacophore alignment on known non-competitive mGluR5 inhibitors applying 4SCan technology, a new lead series was identified and further structurally investigated. K(i)'s as low as around 100 nM were achieved. 相似文献
17.
Tao ZF Li G Tong Y Stewart KD Chen Z Bui MH Merta P Park C Kovar P Zhang H Sham HL Rosenberg SH Sowin TJ Lin NH 《Bioorganic & medicinal chemistry letters》2007,17(21):5944-5951
An extensive structure-activity relationship study of the 3-position of a series of tricyclic pyrazole-based Chk1 inhibitors is described. As a result, 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles (4) and 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2'-carbonitriles (29) emerged as new lead series. Compared with the original lead compound 2, these new leads fully retain the biological activity in both enzymatic inhibition and cell-based assays. More importantly, the new leads 4 and 29 exhibit favorable physicochemical properties such as lower molecular weight, lower Clog P, and the absence of a hydroxyl group. Furthermore, structure-activity relationship studies were performed at the 6- and 7-positions of 4, which led to the identification of ideal Chk1 inhibitors 49, 50, 51, and 55. These compounds not only potently inhibit Chk1 in an enzymatic assay but also significantly potentiate the cytotoxicity of DNA-damaging agents in cell-based assays while they show little single agent activity. A cell cycle analysis by FACS confirmed that these Chk1 inhibitors efficiently abrogate the G2/M and S checkpoints induced by DNA-damaging agent. The current work paved the way to the identification of several potent Chk1 inhibitors with good pharmacokinetics that are suitable for in vivo study with oral dosing. 相似文献
18.
Zareef M Iqbal R De Dominguez NG Rodrigues J Zaidi JH Arfan M Supuran CT 《Journal of enzyme inhibition and medicinal chemistry》2007,22(3):301-308
A series of new benzenesulfonamides, most of which are chiral, incorporating 1, 3, 4-oxadiazole and amino acid moieties have been synthesized. Some of these compounds were screened for antimalarial activity and also evaluated for their ability to inhibit hem polymerization. The electrophoretic analysis indicated that one compound was effective in inhibiting the degradation of hemoglobin. The synthesized compounds were tested in mice infected with Plasmodium berghei. These derivatives have the potential for the development of novel antimalarial lead compounds. 相似文献
19.
Michele Tonelli Vito Boido Paolo La Colla Roberta Loddo Paola Posocco Maria Silvia Paneni Maurizio Fermeglia Sabrina Pricl 《Bioorganic & medicinal chemistry》2010,18(6):2304-2316
Starting from a series of our new 2-phenylbenzimidazole derivatives, shown to be selectively and potently active against the bovine viral diarrhea virus (BVDV), we developed a hierarchical combined experimental/molecular modeling strategy to explore the drug leads for the BVDV RNA-dependent RNA-polymerase. Accordingly, a successful 3D pharmacophore model was developed, characterized by distinct chemical features that may be responsible for the activity of the inhibitors. BVDV mutants resistant to lead compounds in our series were then isolated, and the mutant residues on the viral molecular target, the RNA-dependent RNA-polymerase, were identified. Docking procedures upon pharmacophoric constraints and mutational data were carried out, and the binding affinity of all active compounds for the RdRp were estimated. Given the excellent agreement between in silico and in vitro data, this procedure is currently being employed in the design a new series of more selective and potent BVDV inhibitors. 相似文献
20.
James Kempson Junqing Guo Jagabandhu Das Robert V. Moquin Steven H. Spergel Scott H. Watterson Charles M. Langevine Alaric J. Dyckman Mark Pattoli James R. Burke XiaoXia Yang Kathleen M. Gillooly Kim W. McIntyre Laishun Chen John H. Dodd Murray McKinnon Joel C. Barrish William J. Pitts 《Bioorganic & medicinal chemistry letters》2009,19(10):2646-2649
A new series of tricyclic-based inhibitors of IKK have been derived from an earlier lead compound. The synthesis and structure–activity relationships (SAR) are described. Compound 4k inhibited TNF production in rats stimulated with LPS. 相似文献