共查询到20条相似文献,搜索用时 15 毫秒
1.
Zhe Nie Lihong Shi Chon Lai Shawn M. OConnell Jiangchun Xu Ryan K. Stansfield David J. Hosfield James M. Veal Jeffrey A. Stafford 《Bioorganic & medicinal chemistry letters》2018,28(9):1490-1494
Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1. 相似文献
2.
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
3.
《Bioorganic & medicinal chemistry letters》2020,30(19):127433
Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition. As a result, we identified 30, which exhibited no hERG activity but unfortunately was poorly absorbed in rats and mice. We also identified a SYK chemical probe, 17, which exhibits excellent potency at SYK, and an adequate rodent PK profile to support in vivo efficacy/PD studies. 相似文献
4.
《Bioorganic & medicinal chemistry》2014,22(15):4135-4150
In the last decade the heat shock protein 90 (Hsp90) has emerged as a major therapeutic target and many efforts have been dedicated to the discovery of Hsp90 inhibitors as new potent anticancer agents. Here we report the identification of a novel class of Hsp90 inhibitors by means of a biophysical FAXS-NMR based screening of a library of fragments. The use of X-ray structure information combined with modeling studies enabled the fragment evolution of the initial triazoloquinazoline hit to a class of compounds with nanomolar potency and drug-like properties suited for further lead optimization. 相似文献
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6.
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
7.
Joanne L. Thomson Wesley P. Blackaby Andrew S.R. Jennings Simon C. Goodacre Andrew Pike Steve Thomas Terry A. Brown Alison Smith Gopalan Pillai Leslie J. Street Richard T. Lewis 《Bioorganic & medicinal chemistry letters》2009,19(8):2235-2239
A series of heterocyclic sulfonamides have been developed which are potent and selective inhibitors of hGlyT1. SAR studies to optimise the in vitro and in vivo properties are described. Optimisation of the central scaffold resulted in cyclohexane sulfones 28 and 29, which have good PK properties and show promise for further development. 相似文献
8.
Xu J Wei L Mathvink RJ Edmondson SD Eiermann GJ He H Leone JF Leiting B Lyons KA Marsilio F Patel RA Patel SB Petrov A Scapin G Wu JK Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2006,16(20):5373-5377
A novel series of oxadiazole based amides have been shown to be potent DPP-4 inhibitors. The optimized compound 43 exhibited excellent selectivity over a variety of DPP-4 homologs. 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.
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
11.
Patel D Jain M Shah SR Bahekar R Jadav P Joharapurkar A Dhanesha N Shaikh M Sairam KV Kapadnis P 《Bioorganic & medicinal chemistry letters》2012,22(2):1111-1117
A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a-r) are reported as potent and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro). The lead compound 5o showed potent antidiabetic activity (in vivo), along with improved pharmacokinetic profile. These preliminary results confirm discovery of highly potent and selective PTP1B inhibitors for the treatment of T2DM. 相似文献
12.
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
13.
Mark S. Plummer Joseph Cornicelli Howard Roark Donald J. Skalitzky Charles J. Stankovic Susan Bove Jayvardhan Pandit Annise Goodman James Hicks Aurash Shahripour David Beidler Xiao Kang Lu Brian Sanchez Christopher Whitehead Ron Sarver Timothy Braden Richard Gowan Xi Qiang Shen Sandra Lightle 《Bioorganic & medicinal chemistry letters》2013,23(11):3438-3442
We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition. 相似文献
14.
《Bioorganic & medicinal chemistry》2020,28(1):115128
The human histone demethylases of the KDM4 family have been related to diseases such as prostate and breast cancer. Majority of currently known inhibitors suffer from the low permeability and low selectivity between the enzyme isoforms. In this study, toxoflavin motif was used to design and synthesize new KDM4C inhibitors with improved biological activity and in vitro ADME properties. Inhibitors displayed good passive cellular permeability and metabolic stability. However, diminishing of redox liability and consequently non-specific influence on cell viability still remains a challenge. 相似文献
15.
Zheng C Cao G Xia M Feng H Glenn J Anand R Zhang K Huang T Wang A Kong L Li M Galya L Hughes RO Devraj R Morton PA Rogier DJ Covington M Baribaud F Shin N Scherle P Diamond S Yeleswaram S Vaddi K Newton R Hollis G Friedman S Metcalf B Xue CB 《Bioorganic & medicinal chemistry letters》2011,21(5):1442-1446
We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate. 相似文献
16.
Wendy Lee Daniel F. Ortwine Philippe Bergeron Kevin Lau Lichuan Lin Shiva Malek Jim Nonomiya Zhonghua Pei Kirk D. Robarge Stephen Schmidt Steve Sideris Joseph P. Lyssikatos 《Bioorganic & medicinal chemistry letters》2013,23(18):5097-5104
A series of N-7-methyl-imidazolopyrimidine inhibitors of the mTOR kinase have been designed and prepared, based on the hypothesis that the N-7-methyl substituent on imidazolopyrimidine would impart selectivity for mTOR over the related PI3Kα and δ kinases. The corresponding N-Me substituted pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines also show potent mTOR inhibition with selectivity toward both PI3α and δ kinases. The most potent compound synthesized is pyrazolo[4,3-d]pyrimidine 21c. Compound 21c shows a Ki of 2 nM against mTOR inhibition, remarkable selectivity (>2900×) over PI3 kinases, and excellent potency in cell-based assays. 相似文献
17.
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
18.
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
19.
Raboisson P Lenz O Lin TI Surleraux D Chakravarty S Scholliers A Vermeiren K Delouvroy F Verbinnen T Simmen K 《Bioorganic & medicinal chemistry letters》2007,17(7):1843-1849
Screening of a focused library of TGF beta kinase inhibitors in the cellular HCV replicon model with luciferase read out yielded a number of low micromolar HCV inhibitors. Medicinal chemistry driven optimization resulted in the discovery of 4-[2-(5-bromo-2-fluoro-phenyl)pteridin-4-ylamino]-N-[3-(2- oxopyrrolidin-1-yl)propyl]nicotinamide 36 with a replicon EC(50) of 64nM, associated with a selective kinase inhibitory profile for human JNK kinases 2 and 3 as well as VEGFR-1, 2, and 3 kinases. Moreover, 36 showed an advantageous PK profile in mice. Experiments performed using different replicon constructs suggest that this series of kinase inhibitors might mediate their effect through the HCV non-structural protein 5A (NS5A). 相似文献
20.
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