共查询到20条相似文献,搜索用时 46 毫秒
1.
E Takashiro I Hayakawa T Nitta A Kasuya S Miyamoto Y Ozawa R Yagi I Yamamoto T Shibayama A Nakagawa Y Yabe 《Bioorganic & medicinal chemistry》1999,7(9):2063-2072
The structure-activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing alpha-hydroxy-beta-amino acids is discussed. We demonstrated that substituent groups on the P1 aromatic rings of the inhibitors exert significant influence on their biological activity. Inhibitors bearing an alkyl or a fluorine atom at the meta and para position on their P1 benzene ring were found to be good inhibitors. We also discovered that the substitution positions of the P2 benzamides were crucial for good antiviral potency. In this study, inhibitor 48 was the most potent [IC90 (CEM/HIV-1 IIIB) 27 nM] and showed good pharmacokinetics in rats. 相似文献
2.
Pescatore G Kinzel O Attenni B Cecchetti O Fiore F Fonsi M Rowley M Schultz-Fademrecht C Serafini S Steinkühler C Jones P 《Bioorganic & medicinal chemistry letters》2008,18(20):5528-5532
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in the clinic. Herein we describe the optimization of a series of ketone small molecule HDAC inhibitors leading to potent and selective class I HDAC inhibitors with good dog PK. 相似文献
3.
El Abdellaoui H Varaprasad CV Barawkar D Chakravarty S Maderna A Tam R Chen H Allan M Wu JZ Appleby T Yan S Zhang W Lang S Yao N Hamatake R Hong Z 《Bioorganic & medicinal chemistry letters》2006,16(21):5561-5566
The development of potent, orally bioavailable, and selective series of 5-amino-3-hydroxy-N(1-hydroxypropane-2-yl)isothiazole-4-carboxamidine inhibitors of MEK1 and MEK-2 kinase is described. Optimization of the carboxamidine and the phenoxyaniline group led to the identification of 55 which gave good potency as in vitro MEK1 inhibitors, and good oral exposure in rat. 相似文献
4.
Erra M Moreno I Sanahuja J Andrés M Reinoso RF Lozoya E Pizcueta P Godessart N Castro-Palomino JC 《Bioorganic & medicinal chemistry letters》2011,21(24):7268-7272
The structure–activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model. 相似文献
5.
Cox JM Harper B Mastracchio A Leiting B Sinha Roy R Patel RA Wu JK Lyons KA He H Xu S Zhu B Thornberry NA Weber AE Edmondson SD 《Bioorganic & medicinal chemistry letters》2007,17(16):4579-4583
Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles. 相似文献
6.
Haifeng Tang Reynald K. de Jesus Shawn P. Walsh Yuping Zhu Yan Yan Birgit T. Priest Andrew M. Swensen Magdalena Alonso-Galicia John P. Felix Richard M. Brochu Timothy Bailey Brande Thomas-Fowlkes Xiaoyan Zhou Lee-Yuh Pai Caryn Hampton Melba Hernandez Karen Owens Sophie Roy Alexander Pasternak 《Bioorganic & medicinal chemistry letters》2013,23(21):5829-5832
A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents. 相似文献
7.
Wu Z Fraley ME Bilodeau MT Kaufman ML Tasber ES Balitza AE Hartman GD Coll KE Rickert K Shipman J Shi B Sepp-Lorenzino L Thomas KA 《Bioorganic & medicinal chemistry letters》2004,14(4):909-912
3,7-Diarylsubstituted imidazopyridines were designed and developed as a new class of KDR kinase inhibitors. A variety of imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were identified with good aqueous solubility. 相似文献
8.
Michael B. Wallace Mark E. Adams Toufike Kanouni Clifford D. Mol Douglas R. Dougan Victoria A. Feher Shawn M. O’Connell Lihong Shi Petro Halkowycz Qing Dong 《Bioorganic & medicinal chemistry letters》2010,20(14):4156-4158
A novel series of pyrrole inhibitors of MEK kinase has been developed using structure-based drug design. Optimization of the series led to the identification of potent inhibitors with good pharmaceutical properties. 相似文献
9.
10.
Gilbert AM Bursavich MG Lombardi S Georgiadis KE Reifenberg E Flannery CR Morris EA 《Bioorganic & medicinal chemistry letters》2008,18(24):6454-6457
N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared. Selected compounds 10, 14, 25, and 53 show sub-microM ADAMTS-5 potency and good selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP-13, and MMP-12. Compound 53 shows a good balance of potent ADAMTS-5 inhibition, moderate CYP3A4 inhibition and good rat liver microsome stability. This series of compounds represents progress towards selective ADAMTS-5 inhibitors as disease modifying osteoarthritis agents. 相似文献
11.
《Bioorganic & medicinal chemistry letters》2020,30(13):127197
A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well. 相似文献
12.
Ramtohul YK Powell D Leclerc JP Leger S Oballa R Black C Isabel E Li CS Crane S Robichaud J Guay J Guiral S Zhang L Huang Z 《Bioorganic & medicinal chemistry letters》2011,21(19):5692-5696
Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors. 相似文献
13.
Biological evaluation and docking studies of natural isocoumarins as inhibitors for human kallikrein 5 and 7 总被引:1,自引:0,他引:1
Teixeira TS Freitas RF Abrahão O Devienne KF de Souza LR Blaber SI Blaber M Kondo MY Juliano MA Juliano L Puzer L 《Bioorganic & medicinal chemistry letters》2011,21(20):6112-6115
Human kallikrein 5 and 7 (KLK5 and KLK7) are trypsin-like and chymotrypsin-like serine proteases, respectively, and promising targets for the treatment of skin desquamation, inflammation and cancer. In an effort to develop new inhibitors for these enzymes, we carried out enzymatic inhibition assays and docking studies with three isocoumarin compounds. Some promising inhibitors were uncovered, with vioxanthin and 8,8'-paepalantine being the most potent competitive inhibitors of KLK5 (K(i)=22.9 μM) and KLK7 (K(i)=12.2 μM), respectively. Our docking studies showed a good correlation with the experimental results, and revealed a distinct binding mode for the inhibitors at the binding sites of KLK5 and KLK7. In addition, the docking results suggested that the formation of hydrogen bonds at the oxyanion hole is essential for a good inhibitor. 相似文献
14.
John Liddle Paul Bamborough Michael D. Barker Sebastien Campos Rick P.C. Cousins Geoffrey J. Cutler Heather Hobbs Duncan S. Holmes Chris Ioannou Geoff W. Mellor Mary A. Morse Jeremy J. Payne John M. Pritchard Kathryn J. Smith Daniel T. Tape Caroline Whitworth Richard A. Williamson 《Bioorganic & medicinal chemistry letters》2009,19(9):2504-2508
The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity. 相似文献
15.
Jeffrey W. Corbett Kevin D. Freeman-Cook Richard Elliott Felix Vajdos Francis Rajamohan Darcy Kohls Eric Marr Hailong Zhang Liang Tong Meihua Tu Sharad Murdande Shawn D. Doran Janet A. Houser Wei Song Christopher J. Jones Steven B. Coffey Leanne Buzon Martha L. Minich Kenneth J. Dirico Susan Tapley William Esler 《Bioorganic & medicinal chemistry letters》2010,20(7):2383-2388
Screening Pfizer’s compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype. 相似文献
16.
Wang X Salaski EJ Berger DM Powell D Hu Y Wojciechowicz D Collins K Frommer E 《Bioorganic & medicinal chemistry letters》2011,21(23):6941-6944
Structure-guided design led to the discovery of novel chemical scaffolds for B-Raf inhibitors. Both type I and type II kinase inhibitors have been explored and lead compounds with good potency and excellent selectivity have been identified. 相似文献
17.
Jane L. Wang Scott J. Bowen Barbara A. Schweitzer Heather M. Madsen Joseph McDonald Matthew J. Pelc Ruth E. Tenbrink David Beidler Atli Thorarensen 《Bioorganic & medicinal chemistry letters》2009,19(20):5970-5974
Fatty acid amide hydrolase (FAAH) has attracted significant attention due to its promise as an analgesic target. This has resulted in the discovery of numerous chemical classes as inhibitors of this potential therapeutic target. In this paper we disclose a new series of novel FAAH irreversible azetidine urea inhibitors. In general these compounds illustrate potent activity against the rat FAAH enzyme. Our SAR studies allowed us to optimize this series resulting in the identification of compounds 13 which were potent inhibitors of both human and rat enzyme. This series of compounds illustrated good hydrolase selectivity along with good PK properties. 相似文献
18.
NL Subasinghe E Khalil JM Travins F Ali SK Ballentine HR Hufnagel W Pan K Leonard RF Bone RM Soll CS Crysler N Ninan J Kirkpatrick MX Kolpak KA Diloreto SH Eisennagel ND Huebert CJ Molloy BE Tomczuk MD Gaul 《Bioorganic & medicinal chemistry letters》2012,22(16):5303-5307
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties. 相似文献
19.
《Bioscience Hypotheses》2008,1(6):334-335
DNA methylation changes in cancer activate and de-activate both oncogenes and anti-oncogenes. Global methylation inhibitors could therefore do as much harm as good, and more specific methylase inhibitors are needed to have a chance of being effective anti-cancer drugs. 相似文献
20.
R J Cherney L Wang D T Meyer C B Xue E C Arner R A Copeland M B Covington K D Hardman Z R Wasserman B D Jaffee C P Decicco 《Bioorganic & medicinal chemistry letters》1999,9(9):1279-1284
Several macrocyclic, hydroxamate derivatives were synthesized and evaluated as inhibitors of matrix metalloproteinases (MMPs) and tumour necrosis factor-alpha (TNF-alpha) production. These macrocycles are anti-succinate based inhibitors linked from P1 to P2'. A variety of functionality was installed at the P1-P2' linkage, which gave inhibitors that displayed excellent MMP inhibition and good TNF-alpha suppression. 相似文献