共查询到20条相似文献,搜索用时 31 毫秒
1.
Xiaocong M. Ye Andrei W. Konradi Minghua Sun Shendong Yuan Danielle L. Aubele Michael Dappen Darren Dressen Albert W. Garofalo Jacek J. Jagodzinski Lee Latimer Gary D. Probst Hing L. Sham David Wone Ying-zi Xu Daniel Ness Elizabeth Brigham Grace T. Kwong Chris Willtis Guriqbal S. Basi 《Bioorganic & medicinal chemistry letters》2013,23(4):996-1000
Structure–activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted. 相似文献
2.
Li H Xu R Cole D Clader JW Greenlee WJ Nomeir AA Song L Zhang L 《Bioorganic & medicinal chemistry letters》2010,20(22):6606-6609
Design and synthesis of cis-2,6-disubstituted N-arylsulfonyl morpholines as novel γ-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. Several different small alkyl groups are installed on the left-hand side to lower the CYP3A4 liability while maintaining excellent in vitro potency. 相似文献
3.
Daniel Oehlrich Frederik J.R. Rombouts Didier Berthelot François P. Bischoff Michel A.J. De Cleyn Libuse Jaroskova Gregor Macdonald Marc Mercken Michel Surkyn Andrés A. Trabanco Gary Tresadern Sven Van Brandt Adriana I. Velter Tongfei Wu Harrie J.M. Gijsen 《Bioorganic & medicinal chemistry letters》2013,23(17):4794-4800
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer’s drug which demonstrated high in vitro and in vivo potency against Aβ42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series. 相似文献
4.
François P. Bischoff Adriana Ingrid Velter Garrett Minne Serge Pieters Didier Berthelot Michel De Cleyn Harrie J.M. Gijsen Gregor Macdonald Michel Surkyn Sven Van Brandt Yves Van Roosbroeck Chiara Zavattaro Marc Mercken Nigel Austin Deborah Dhuyvetter Herman Borghys Ishtiyaque Ahmad Swapan Kumar Samanta 《Bioorganic & medicinal chemistry letters》2019,29(14):1737-1745
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile. 相似文献
5.
Simeon Bowers Gary D. Probst Anh P. Truong Roy K. Hom Andrei W. Konradi Hing L. Sham Albert W. Garofalo Karina Wong Erich Goldbach Kevin P. Quinn John-Michael Sauer William Wallace Lan Nguyen Susanna S. Hemphill Michael P. Bova Guriqbal S. Basi 《Bioorganic & medicinal chemistry letters》2009,19(24):6952-6956
The structural modification of a series of [3.3.1] bicyclic sulfonamide based γ-secretase inhibitors is described. Appropriate substitution on the bicyclic scaffold provides a significant increase in the metabolic stability of the compounds resulting in an improved in vivo metabolic profile. 相似文献
6.
Xiaojun Zhang Peter W. Glunz Wen Jiang Aaron Schmitt Makenzie Newman Frank A. Barbera Jeffery M. Bozarth Alan R. Rendina Anzhi Wei Xiao Wen Karen A. Rossi Joseph M. Luettgen Pancras C. Wong Robert M. Knabb Ruth R. Wexler E. Scott Priestley 《Bioorganic & medicinal chemistry letters》2013,23(6):1604-1607
Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF–FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity. 相似文献
7.
Anh P. Truong Danielle L. Aubele Gary D. Probst Martin L. Neitzel Chris M. Semko Simeon Bowers Darren Dressen Roy K. Hom Andrei W. Konradi Hing L. Sham Albert W. Garofalo Pamela S. Keim Jing Wu Michael S. Dappen Karina Wong Erich Goldbach Kevin P. Quinn John-Michael Sauer Elizabeth F. Brigham William Wallace Guriqbal Basi 《Bioorganic & medicinal chemistry letters》2009,19(17):4920-4923
In this Letter, we report our strategy to design potent and metabolically stable γ-secretase inhibitors that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose. 相似文献
8.
《Bioorganic & medicinal chemistry letters》2020,30(20):127479
Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold. 相似文献
9.
Yiping Zhu Kun Xiao Lanping Ma Bin Xiong Yan Fu Haiping Yu Wei Wang Xin Wang Dingyu Hu Hongli Peng Jingya Li Qi Gong Qian Chai Xican Tang Haiyan Zhang Jia Li Jingkang Shen 《Bioorganic & medicinal chemistry》2009,17(4):1600-1613
To explore novel effective drugs for the treatment of Alzheimer’s disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and β-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC50 = 0.567 μM; AChE: IC50 = 1.83 μM), and also showed excellent inhibitory effects on Aβ production of APP transfected HEK293 cells (IC50 = 98.7 nM) and mild protective effect against hydrogen peroxide (H2O2)-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Aβ1–40 production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients. 相似文献
10.
Ruo Xu David Cole Ted Asberom Tom Bara Chad Bennett Duane A. Burnett John Clader Martin Domalski William Greenlee Lynn Hyde Hubert Josien Hongmei Li Mark McBriar Brian McKittrick Andrew T. McPhail Dmitri Pissarnitski Li Qiang Murali Rajagopalan Thavalakulamgar Sasikumar Jing Su Zhiqiang Zhao 《Bioorganic & medicinal chemistry letters》2010,20(8):2591-2596
A novel series of tricyclic γ-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous γ-secretase inhibitors. 相似文献
11.
T.K. Sasikumar Duane A. Burnett Theodros Asberom Wen-Lian Wu Chad Bennett David Cole Ruo Xu William J. Greenlee John Clader Lili Zhang Lynn Hyde 《Bioorganic & medicinal chemistry letters》2010,20(12):3645-3648
Complex tetracyclic sulfones were designed as γ-secretase inhibitors and a stereoselective synthesis was achieved. γ-Secretase activity was seen predominately in the (?) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency. 相似文献
12.
Brodney MA Auperin DD Becker SL Bronk BS Brown TM Coffman KJ Finley JE Hicks CD Karmilowicz MJ Lanz TA Liston D Liu X Martin BA Nelson RB Nolan CE Oborski CE Parker CP Richter KE Pozdnyakov N Sahagan BG Schachter JB Sokolowski SA Tate B Wood DE Wood KM Van Deusen JW Zhang L 《Bioorganic & medicinal chemistry letters》2011,21(9):2637-2640
A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aβ in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aβ EC50 lead to the identification of compound 14f (PF-3084014) which was selected for clinical development. 相似文献
13.
Harikishore Pingali Mukul Jain Shailesh Shah Pandurang Zaware Pankaj Makadia Suresh Pola Baban Thube Darshit Patel Pravin Patil Priyanka Priyadarshini Dinesh Suthar Maanan Shah Suresh Giri Pankaj Patel 《Bioorganic & medicinal chemistry letters》2010,20(3):1156-1161
Bis-oximinoalkanoic acid derivatives were designed and synthesized to aid in the characterization of selective PPARα agonists by replacing the oxazole ring with flexible oximino group in the lipophilic tail part of a previously reported compound 3. Selected compounds 9d and 9m showed excellent potency and high selectivity towards PPARα in vitro. These compounds found effective in reducing serum triglycerides (TG) in vivo. 相似文献
14.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):846-867
AbstractBecause of the pivotal role of cyclooxygenase (COX) in the inflammatory processes, non-steroidal anti-inflammatory drugs (NSAIDs) that suppress COX activities have been used clinically for the treatment of inflammatory diseases/syndromes; however, traditional NSAIDs exhibit serious side-effects such as gastrointestinal damage and hyper sensitivity owing to their COX-1 inhibition. Also, COX-2 inhibition-derived suppressive or preventive effects against initiation/proliferation/invasion/motility/recurrence/metastasis of various cancers/tumours such as colon, gastric, skin, lung, liver, pancreas, breast, prostate, cervical and ovarian cancers are significant. In this study, design, synthesis and structure–activity relationship (SAR) of various novel {2-[(2-, 3- and/or 4-substituted)-benzoyl, (bicyclic heterocycloalkanophenyl)carbonyl or cycloalkanecarbonyl]-(5- or 6-substituted)-1H-indol-3-yl}acetic acid analogues were investigated to seek and identify various chemotypes of potent and selective COX-2 inhibitors for the treatment of inflammatory diseases, resulting in the discovery of orally potent agents in the peripheral-inflammation model rats. The SARs and physicochemical properties for the analogues are described as significant findings. For graphical abstract: see Supplementary Material. (www.informahealthcare.com/enz) 相似文献
15.
Pettersson M Johnson DS Subramanyam C Bales KR am Ende CW Fish BA Green ME Kauffman GW Lira R Mullins PB Navaratnam T Sakya SM Stiff CM Tran TP Vetelino BC Xie L Zhang L Pustilnik LR Wood KM O'Donnell CJ 《Bioorganic & medicinal chemistry letters》2012,22(8):2906-2911
We report the discovery and optimization of a novel series of dihydrobenzofuran amides as γ-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain Aβ42 lowering activity at 100 mg/kg po dose. 相似文献
16.
Shengqiang Shen Wei Chen Lili Dong Huizhe Lu 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):445-452
GH20 human β-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these β-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki?=?0.91?µM against hsHexB; Ki?>?100?µM against hOGA) and compound 15b (Ki?=?3.76?µM against hOGA; Ki?=?30.42?µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure–activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific β-N-acetylhexosaminidase inhibitors. 相似文献
17.
Yosuke Ota Shin Miyamura Misaho Araki Yukihiro Itoh Shusuke Yasuda Mitsuharu Masuda Tomoyuki Taniguchi Yoshihiro Sowa Toshiyuki Sakai Kenichiro Itami Junichiro Yamaguchi Takayoshi Suzuki 《Bioorganic & medicinal chemistry》2018,26(3):775-785
Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors. 相似文献
18.
AK Ghosh S Pandey S Gangarajula S Kulkarni X Xu KV Rao X Huang J Tang 《Bioorganic & medicinal chemistry letters》2012,22(17):5460-5465
Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13nM) and cellular (IC(50)=21nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site. 相似文献
19.
Jun Pu Anthony F. Kreft Suzan H. Aschmies Kevin P. Atchison Joshua Berkowitz Thomas J. Caggiano Micheal Chlenov George Diamantidis Boyd L. Harrison Yun Hu Donna Huryn J. Steven Jacobsen Mei Jin Kerri Lipinski Peimin Lu Robert L. Martone Koi Morris June Sonnenberg-Reines Dave R. Riddell Joan Sabalski Lynn Resnick 《Bioorganic & medicinal chemistry》2009,17(13):4708-4717
γ-Secretase inhibitors have been shown to reduce the production of β-amyloid, a component of the plaques that are found in brains of patients with Alzheimer’s disease. A novel series of heterocyclic sulfonamide γ-secretase inhibitors that reduce β-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative γ-secretase substrate. 相似文献
20.
《Bioorganic & medicinal chemistry letters》2014,24(1):378-381
The design, synthesis, and SAR of cyclic diamines as novel γ secretase modulators (GSMs) are presented in this Letter. Starting from information in the literature and in-house cyclic diamines library, we have found a 3(S)-aminopiperidine as a potent structure for lowering Aβ42 production both in vitro and in vivo. 相似文献