共查询到20条相似文献,搜索用时 0 毫秒
1.
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
2.
Peters JU Galley G Jacobsen H Czech C David-Pierson P Kitas EA Ozmen L 《Bioorganic & medicinal chemistry letters》2007,17(21):5918-5923
Structural modifications of the gamma-secretase inhibitor, LY411575, led to a malonamide analogue (S),(S)-1 with potent inhibitory activity in vitro, but disappointing activity in a mouse model of Alzheimer's disease. Identification and replacement of a metabolically labile position provided an improved compound (R/S),(S)-13 with high in vitro activity (IC(50)=1.7 nM), and in vivo activity after oral administration (MED=3 mg/kg). Further modifications gave an equipotent carbamate analogue 14 with improved molecular properties. 相似文献
3.
Côté B Boulet L Brideau C Claveau D Ethier D Frenette R Gagnon M Giroux A Guay J Guiral S Mancini J Martins E Massé F Méthot N Riendeau D Rubin J Xu D Yu H Ducharme Y Friesen RW 《Bioorganic & medicinal chemistry letters》2007,17(24):6816-6820
Phenanthrene imidazole 3 (MF63) has been identified as a novel potent, selective, and orally active mPGES-1 inhibitor. This new series was developed by lead optimization of a hit from an internal HTS campaign. Compound 3 is significantly more potent than the previously reported indole carboxylic acid 1 with an A549 whole cell IC50 of 0.42 μM (50% FBS) and a human whole blood IC50 of 1.3 μM. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model when orally dosed at 30 and 100 mg/kg. 相似文献
4.
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
5.
Ducharme Y Friesen RW Blouin M Côté B Dubé D Ethier D Frenette R Laliberté F Mancini JA Masson P Styhler A Young RN Girard Y 《Bioorganic & medicinal chemistry letters》2003,13(11):1923-1926
The synthesis and the phosphodiesterase-4 (PDE4) inhibitory activity of 2-pyridinemethanol derivatives is described. The evaluation of the structure-activity relationship (SAR) in this series of novel PDE4 inhibitors led to the identification of compound 9 which exhibits excellent in vitro activity, desirable pharmacokinetic parameters and good efficacy in animal models of bronchoconstriction. 相似文献
6.
Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors.
R Frenette J H Hutchinson S Léger M Thérien C Brideau C C Chan S Charleson D Ethier J Guay T R Jones M McAuliffe H Piechuta D Riendeau P Tagari Y Girard 《Bioorganic & medicinal chemistry letters》1999,9(16):2391-2396
This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. Lead optimization culminated in (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(pyridin-2-ylmethoxy)-ind ol-2-yl]-2,2-dimethylpropanoic acid (18k), as a potent inhibitor of leukotriene biosynthesis that is well absorbed and active in functional models. 相似文献
7.
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
8.
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
9.
Atkinson KA Beretta EE Brown JA Castrodad M Chen Y Cosgrove JM Du P Litchfield J Makowski M Martin K McLellan TJ Neagu C Perry DA Piotrowski DW Steppan CM Trilles R 《Bioorganic & medicinal chemistry letters》2011,21(6):1621-1625
A potent, small molecule inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo was identified. Starting from a low MW acyl guanidine (5a), identified with a RapidFire High-Throughput Mass Spectrometry (RF-MS) assay, iterative library design was used to rapidly probe the amide and tail regions of the molecule. Singleton synthesis was used to probe core changes. Biological evaluation of a SCD inhibitor (5b) included in vitro potency at SCD-1 and in vivo modulation of the plasma desaturation index (DI) in rats on a low essential fatty acid (LEFA) diet. In addition to dose-dependent decrease in DI, effects on rodent ocular tissue were noted. Therefore, in rat, these SCD inhibitors only recapitulate a portion of phenotype exhibited by the SCD-1 knockout mouse. 相似文献
10.
Baxter A Brough S Cooper A Floettmann E Foster S Harding C Kettle J McInally T Martin C Mobbs M Needham M Newham P Paine S St-Gallay S Salter S Unitt J Xue Y 《Bioorganic & medicinal chemistry letters》2004,14(11):2817-2822
A hit-to-lead optimisation programme was carried out on the thiophenecarboxamide high throughput screening hits 1 and 2 resulting in the discovery of the potent and orally bioavailable IKK-2 inhibitor 22. 相似文献
11.
Tomoharu Tsukada Osamu Kanno Takahiro Yamane Jun Tanaka Taishi Yoshida Akira Okuno Takeshi Shiiki Mizuki Takahashi Takahide Nishi 《Bioorganic & medicinal chemistry》2010,18(14):5346-5351
With the aim of exploring the effect of tricyclic-based FBPase inhibitors in cells and in vivo, a series of prodrugs of tricyclic phosphonates was designed and synthesized. Introducing prodrug moieties into tricyclic-based phosphonates led to the discovery of prodrug 15c, which strongly inhibited glucose production in monkey hepatocytes. Furthermore, prodrug 15c lowered blood glucose levels in fasted cynomolgus monkeys. 相似文献
12.
Xiao Ding Xuedong Dai Kai Long Cheng Peng Daniele Andreotti Paul Bamborough Andrew J. Eatherton Colin Edge Karamjit S. Jandu Paula L. Nichols Oliver J. Philps Luigi Piero Stasi Zehong Wan Jia-Ning Xiang Kelly Dong Pamela Dossang Ming-Hsun Ho Yi Li Feng Ren 《Bioorganic & medicinal chemistry letters》2017,27(17):4034-4038
Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson’s disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability. 相似文献
13.
Victor J. Cee Alan C. Cheng Karina Romero Steve Bellon Christopher Mohr Douglas A. Whittington Annette Bak James Bready Sean Caenepeel Angela Coxon Holly L. Deak Jenne Fretland Yan Gu Brian L. Hodous Xin Huang Joseph L. Kim Jasmine Lin Alexander M. Long Hanh Nguyen Philip R. Olivieri Stephanie Geuns-Meyer 《Bioorganic & medicinal chemistry letters》2009,19(2):424-427
Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase. 相似文献
14.
Devadas B Selness SR Xing L Madsen HM Marrufo LD Shieh H Messing DM Yang JZ Morgan HM Anderson GD Webb EG Zhang J Devraj RV Monahan JB 《Bioorganic & medicinal chemistry letters》2011,21(13):3856-3860
A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (>90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-α in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model. 相似文献
15.
Birch AM Kenny PW Oikonomakos NG Otterbein L Schofield P Whittamore PR Whalley DP 《Bioorganic & medicinal chemistry letters》2007,17(2):394-399
A series of substituted 3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a rat model. X-ray crystallographic data are presented, showing an unexpected variety of binding orientations at the dimer interface site. 相似文献
16.
Jitendra A. Sattigeri Malvika Garg Pragya Bhateja Ajay Soni Abdul Rehman Abdul Rauf Mahendrakumar Gupta Mahesh S. Deshmukh Tarun Jain Nidhi Alekar Tarani Kanta Barman Paras Jha Tridib Chaira Ramesh B. Bambal Dilip J. Upadhyay Takahide Nishi 《Bioorganic & medicinal chemistry letters》2018,28(17):2993-2997
FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice. 相似文献
17.
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
18.
Rainer Gewald Christian Grunwald Ute Egerland 《Bioorganic & medicinal chemistry letters》2013,23(15):4308-4314
Expanding on HTS hit 4 afforded a series of [1,3,5]triazine derivatives as novel PDE4 inhibitors. The SAR development and optimization process with the emphasis on ligand efficiency and physicochemical properties led to the discovery of compound 44 as a potent, selective and orally active PDE4 inhibitor. 相似文献
19.
Yoshihiro Kato Motoji Kawasaki Tomohiro Nigo Shunya Nakamura Akira Fusano Yasuhiro Teranishi Mari N. Ito Takaaki Sumiyoshi 《Bioorganic & medicinal chemistry》2013,21(18):5851-5854
A series of 2,3-disubstituted pyridines were synthesized and evaluated for their PDE4 inhibitory activity. We successfully modified undesirable cyano group of initial lead compound 2 to 4-pyridyl group with improvement of in vitro efficacy and optimized the position of nitrogen atoms in pyridine moiety and alkylene linker. The most potent compound showed significant efficacy in animal models of asthma and inflammation. 相似文献
20.
Shinya Nagashima Takeshi Hondo Hiroshi Nagata Takashi Ogiyama Jun Maeda Hiroaki Hoshii Toru Kontani Sadao Kuromitsu Keiko Ohga Masaya Orita Kazuki Ohno Ayako Moritomo Koichi Shiozuka Masako Furutani Makoto Takeuchi Mitsuaki Ohta Shin-ichi Tsukamoto 《Bioorganic & medicinal chemistry》2009,17(19):6926-6936