共查询到20条相似文献,搜索用时 0 毫秒
1.
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
2.
Tang J Hamajima T Nakano M Sato H Dickerson SH Lackey KE 《Bioorganic & medicinal chemistry letters》2008,18(16):4610-4614
The synthesis of a 7-azaindole series of novel, potent B-Raf kinase inhibitors using knowledge-based design was carried out. Compound 6h exhibits not only excellent potency in both the enzyme assay (IC(50)=2.5 nM) and the cellular assay (IC(50)=63 nM), but also has an outstanding selectivity profile against other kinases. 相似文献
3.
Bingham AH Davenport RJ Gowers L Knight RL Lowe C Owen DA Parry DM Pitt WR 《Bioorganic & medicinal chemistry letters》2004,14(2):409-412
A novel series of aminopyrimidine IKK2 inhibitors have been developed which show excellent in vitro inhibition of this enzyme and good selectivity over the IKK1 isoform. The relative potency and selectivity of these compounds has been rationalized using QSAR and structure-based modelling. 相似文献
4.
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
5.
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
6.
Duffy JL Kirk BA Wang L Eiermann GJ He H Leiting B Lyons KA Patel RA Patel SB Petrov A Scapin G Wu JK Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2007,17(10):2879-2885
A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented. 相似文献
7.
Quan ML Han Q Fevig JM Lam PY Bai S Knabb RM Luettgen JM Wong PC Wexler RR 《Bioorganic & medicinal chemistry letters》2006,16(7):1795-1798
We have previously reported on a series of aminobenzisoxazoles as potent, selective, and orally bioavailable factor Xa inhibitors, which culminated in the discovery of razaxaban. Herein, we describe another approach to improve factor Xa inhibitory potency and pharmacokinetic profile by incorporating basic and water soluble functionalities on the terminal ring of the P4 biaryl group found in our earlier Xa inhibitors. This approach resulted in a series of potent, selective, and orally bioavailable factor Xa inhibitors. 相似文献
8.
Dai C Li D Popovici-Muller J Zhao L Girijavallabhan VM Rosner KE Lavey BJ Rizvi R Shankar BB Wong MK Guo Z Orth P Strickland CO Sun J Niu X Chen S Kozlowski JA Lundell DJ Piwinski JJ Shih NY Siddiqui MA 《Bioorganic & medicinal chemistry letters》2011,21(10):3172-3176
TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability. 相似文献
9.
Xu J Wei L Mathvink R Edmondson SD Mastracchio A Eiermann GJ He H Leone JF Leiting B Lyons KA Marsilio F Patel RA Petrov A Wu JK Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2006,16(5):1346-1349
anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. The optimized compound exhibited good pharmacokinetic profiles in three preclinical species. 相似文献
10.
Matthew A.J. Duncton Eugene L. Piatnitski Chekler Reeti Katoch-Rouse Dan Sherman Wai C. Wong Leon M. Smith Joel K. Kawakami Alexander S. Kiselyov Daniel L. Milligan Chris Balagtas Yaron R. Hadari Ying Wang Sheetal N. Patel Robin L. Rolster James R. Tonra David Surguladze Stan Mitelman Paul Kussie Peter Bohlen Jacqueline F. Doody 《Bioorganic & medicinal chemistry》2009,17(2):731-740
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice. 相似文献
11.
Hwei-Ru Tsou Gloria MacEwan Gary Birnberg Nan Zhang Natasja Brooijmans Lourdes Toral-Barza Irwin Hollander Semiramis Ayral-Kaloustian Ker Yu 《Bioorganic & medicinal chemistry letters》2010,20(7):2259-2263
A series of 5-ureidobenzofuranones was discovered as potent and selective inhibitors of mTOR with good cellular activity. Molecular modeling studies revealed several hydrogen bond interactions of the ureido group with the enzyme at the ATP-binding site. Furthermore, modeling showed that the ureido group is best situated at C-5 of the benzofuranone. Syntheses of 4-ureido and 5-ureidobenzofuranones are presented. 相似文献
12.
Saravanan Parthasarathy Kenneth Henry Huaxing Pei Josh Clayton Mark Rempala Deidre Johns Oscar De Frutos Pablo Garcia Carlos Mateos Sehila Pleite Yong Wang Stephanie Stout Bradley Condon Sheela Ashok Zhohai Lu William Ehlhardt Tom Raub Mei Lai Timothy P. Burkholder 《Bioorganic & medicinal chemistry letters》2018,28(10):1887-1891
During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model. 相似文献
13.
Sperandio D Tai VW Lohman J Hirschbein B Mendonca R Lee CS Spencer JR Janc J Nguyen M Beltman J Sprengeler P Scheerens H Lin T Liu L Gadre A Kellogg A Green MJ McGrath ME 《Bioorganic & medicinal chemistry letters》2006,16(15):4085-4089
The synthesis of novel [1,2,4]oxadiazoles and their structure-activity relationship (SAR) for the inhibition of tryptase and related serine proteases is presented. Elaboration of the P'-side afforded potent, selective, and orally bioavailable tryptase inhibitors. 相似文献
14.
Duan JJ Chen L Lu Z Xue CB Liu RQ Covington MB Qian M Wasserman ZR Vaddi K Christ DD Trzaskos JM Newton RC Decicco CP 《Bioorganic & medicinal chemistry letters》2008,18(1):241-246
Beta-benzamido hydroxamic acids were discovered as potent TACE inhibitors. A computer model was constructed to help understanding the binding activities and guiding SAR study. SAR optimization led to the discovery of compound 30 which met all in vitro and in vivo criteria for the program and was selected for further evaluation. 相似文献
15.
Marc Gerspacher Pascal Furet Carole Pissot-Soldermann Christoph Gaul Philipp Holzer Eric Vangrevelinghe Marc Lang Dirk Erdmann Thomas Radimerski Catherine H. Regnier Patrick Chene Alain De Pover Francesco Hofmann Fabienne Baffert Thomas Buhl Reiner Aichholz Francesca Blasco Ralf Endres Jörg Trappe Peter Drueckes 《Bioorganic & medicinal chemistry letters》2010,20(5):1724-1727
A series of novel benzoxazole derivatives has been designed and shown to exhibit attractive JAK2 inhibitory profiles in biochemical and cellular assays, capable of delivering compounds with favorable PK properties in rats. Synthesis and structure–activity relationship data are also provided. 相似文献
16.
Xiao Ding Luigi Piero Stasi Ming-Hsun Ho Baowei Zhao Hailong Wang Kai Long Qiongfeng Xu Yingxia Sang Changhui Sun Huan Hu Haihua Yu Zehong Wan Lizhen Wang Colin Edge Qian Liu Yi Li Kelly Dong Xiaoming Guan Feng Ren 《Bioorganic & medicinal chemistry letters》2018,28(9):1615-1620
Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson’s disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100?mg/kg) and mice (45?mg/kg) following oral administration. 相似文献
17.
Gauthier JY Black WC Courchesne I Cromlish W Desmarais S Houle R Lamontagne S Li CS Massé F McKay DJ Ouellet M Robichaud J Truchon JF Truong VL Wang Q Percival MD 《Bioorganic & medicinal chemistry letters》2007,17(17):4929-4933
Highly potent, selective, and bioavailable inhibitors of human, mouse, or rat cathepsin S are described. The key structural features combine a sulfonyl moiety attached to a large group in P2 and a small substituent in P3. 相似文献
18.
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
19.
Ambler J Baker E Bentley D Brown L Butler K Butler P Farr D Dunnet K Le Grand D Hayler J Janus D Jones D Menear K Mercer M Smith G Talbot M Tweed M 《Bioorganic & medicinal chemistry letters》1999,9(5):737-742
The application of selection criteria, based on potency and physicochemical parameters, to a candidate library of thrombin inhibitors is described. The utility of the approach is exemplified by the discovery of a potent, selective and bioavailable thrombin inhibitor 62. 相似文献
20.
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