共查询到20条相似文献,搜索用时 86 毫秒
1.
Andrew Fensome Joel Goldberg Casey C. McComas Eugene J. Trybulski Richard P. Woodworth Darlene C. Deecher Garth T. Whiteside Puwen Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1555-1558
Two related series of selective norepinephrine reuptake inhibitors were synthesized based on 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide or 3,4-dihydrosulfostyril cores, and screened for monoamine reuptake inhibition. Structure–activity relationships were determined for the series’ in vitro potency and selectivity versus serotonin or dopamine transporter inhibition, and analogs based on both cores were identified as potent and selective NRIs. The 3,4-dihydrosulfostyril series was further tested for microsome stability, and compound 16j, which was optimized for both potency and stability, showed efficacy in an in vivo model of thermoregulatory dysfunction. 相似文献
2.
Walker DP Bi FC Kalgutkar AS Bauman JN Zhao SX Soglia JR Aspnes GE Kung DW Klug-McLeod J Zawistoski MP McGlynn MA Oliver R Dunn M Li JC Richter DT Cooper BA Kath JC Hulford CA Autry CL Luzzio MJ Ung EJ Roberts WG Bonnette PC Buckbinder L Mistry A Griffor MC Han S Guzman-Perez A 《Bioorganic & medicinal chemistry letters》2008,18(23):6071-6077
The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay. 相似文献
3.
Shrader WD Kolesnikov A Burgess-Henry J Rai R Hendrix J Hu H Torkelson S Ton T Young WB Katz BA Yu C Tang J Cabuslay R Sanford E Janc JW Sprengeler PA 《Bioorganic & medicinal chemistry letters》2006,16(6):1596-1600
Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa. 相似文献
4.
Frank Lovering Steve Kirincich Weiheng Wang Kerry Combs Lynn Resnick Joan E. Sabalski John Butera Julie Liu Kevin Parris J.B. Telliez 《Bioorganic & medicinal chemistry》2009,17(9):3342-3351
A novel series of inhibitors for mitogen activated protein kinase-activated protein kinase 2 (MK-2) are reported. These squarate based inhibitors were identified via a high-throughput screen. An MK2 co-structure with the starting ligand was obtained and a structure based approach was followed to optimize potency and selectivity. 相似文献
5.
Qingjie Liu Douglas G. Batt Charu Chaudhry Jonathan S. Lippy Mark A. Pattoli Neha Surti Songmei Xu Percy H. Carter James R. Burke Joseph A. Tino 《Bioorganic & medicinal chemistry letters》2018,28(18):3080-3084
Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight. 相似文献
6.
《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
7.
Ren L Laird ER Buckmelter AJ Dinkel V Gloor SL Grina J Newhouse B Rasor K Hastings G Gradl SN Rudolph J 《Bioorganic & medicinal chemistry letters》2012,22(2):1165-1168
Herein we describe a novel series of ATP competitive B-Raf inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with improved physicochemical and pharmacokinetic properties. 相似文献
8.
Ren L Ahrendt KA Grina J Laird ER Buckmelter AJ Hansen JD Newhouse B Moreno D Wenglowsky S Dinkel V Gloor SL Hastings G Rana S Rasor K Risom T Sturgis HL Voegtli WC Mathieu S 《Bioorganic & medicinal chemistry letters》2012,22(10):3387-3391
Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. 相似文献
9.
Liu Q Wang J Kang SA Thoreen CC Hur W Choi HG Waller DL Sim T Sabatini DM Gray NS 《Bioorganic & medicinal chemistry letters》2011,21(13):4036-4040
Starting from small molecule mTOR inhibitor Torin1, replacement of the piperazine ring with a phenyl ring resulted in a new series of mTOR inhibitors (as exemplified by 10) that showed superior potency and selectivity for mTOR, along with significantly improved mouse liver microsome stability and a longer in vivo half-life. 相似文献
10.
Sarwat Chowdhury Yen Ting Chen Xingang Fang Wayne Grant Jennifer Pocas Michael D. Cameron Claudia Ruiz Li Lin HaJeung Park Thomas Schröter Thomas D. Bannister Philip V. LoGrasso Yangbo Feng 《Bioorganic & medicinal chemistry letters》2013,23(6):1592-1599
SAR and lead optimization studies for Rock inhibitors based on amino acid-derived quinazolines are described. Studies demonstrated that these amino acid derived quinazolinones were mainly pan-Rock (I & II) inhibitors. While selectivity against other kinases could be achieved, selectivity for most of these compounds against PKA was not achieved. This is distinct from Rock inhibitors based on non-amino acid derived quinazolinones, where high selectivity against PKA could be obtained.22 The inhibitors presented here in some cases possessed sub-nanomolar inhibition of Rock, nanomolar potency in ppMLC cell based assays, low to fair cytochrome P-450 inhibition, and good human microsomal stability. 相似文献
11.
Cailan Wang James R. Corte Karen A. Rossi Jeffrey M. Bozarth Yiming Wu Steven Sheriff Joseph E. Myers Joseph M. Luettgen Dietmar A. Seiffert Ruth R. Wexler Mimi L. Quan 《Bioorganic & medicinal chemistry letters》2017,27(17):4056-4060
A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, and good potency in the activated partial thromboplastin time (aPTT) clotting assay. 相似文献
12.
Baettig U Brown L Brundish D Dell C Furzer A Garman S Janus D Kane PD Smith G Walker CV Cockcroft X Ambler J Mitchelson A Talbot MD Tweed M Wills N 《Bioorganic & medicinal chemistry letters》2000,10(14):1563-1566
A series of monocyclic and bicyclic amino acids have been synthesised and incorporated into thrombin inhibitors based on CGH728, an analogue of the Mitsubishi compound MD805. Benzthiazolylalanine (Bta) was found to be a good non-polar substitute for arginine at the P1 position, yielding compounds with low nanomolar potency and good selectivity for thrombin. 相似文献
13.
Setti EL Davis D Janc JW Jeffery DA Cheung H Yu W 《Bioorganic & medicinal chemistry letters》2005,15(5):1529-1534
The synthesis of a series of highly potent and selective inhibitors of cathepsin K based on the 3,4-disubstituted azetidin-2-one warhead is reported. A high degree of potency and selectivity was achieved by introducing a basic nitrogen into the distal part of the P3 element of the molecule. Data from kinetic and mass spectrometry experiments are consistent with the interpretation that compounds of this series transiently acylate the sulfhydrile of cathepsin K. 相似文献
14.
Le Brazidec JY Pasis A Tam B Boykin C Wang D Marcotte DJ Claassen G Chong JH Chao J Fan J Nguyen K Silvian L Ling L Zhang L Choi M Teng M Pathan N Zhao S Li T Taveras A 《Bioorganic & medicinal chemistry letters》2012,22(12):4033-4037
This Letter reports the optimization of a pyrrolopyrimidine series as dual inhibitors of Aurora A/B kinases. This series derived from a pyrazolopyrimidine series previously reported as inhibitors of aurora kinases and CDKs. In an effort to improve the selectivity of this chemotype, we switched to the pyrrolopyrimidine core which allowed functionalization on C-2. In addition, the modeling rationale was based on superimposing the structures of Aurora-A kinase and CDK2 which revealed enough differences leading to a path for selectivity improvement. The synthesis of the new series of pyrrolopyrimidine analogs relied on the development of a different route for the two key intermediates 7 and 19 which led to analogs with both tunable activity against CDK1 and maintained cell potency. 相似文献
15.
Letavic MA Axt MZ Barberia JT Carty TJ Danley DE Geoghegan KF Halim NS Hoth LR Kamath AV Laird ER Lopresti-Morrow LL McClure KF Mitchell PG Natarajan V Noe MC Pandit J Reeves L Schulte GK Snow SL Sweeney FJ Tan DH Yu CH 《Bioorganic & medicinal chemistry letters》2002,12(10):1387-1390
A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood. 相似文献
16.
Design,synthesis and biological activity of beta-carboline-based type-5 phosphodiesterase inhibitors 总被引:1,自引:0,他引:1
Maw GN Allerton CM Gbekor E Million WA 《Bioorganic & medicinal chemistry letters》2003,13(8):1425-1428
The SAR of a series of beta-carboline derived type 5 phosphodiesterase inhibitors has been explored and we have discovered compounds with excellent levels of PDE5 potency and selectivity over PDE6. However, the series exhibits low levels of selectivity over PDE11, a phosphodiesterase with unknown function. 相似文献
17.
Kim YH Choi H Lee J Hwang IC Moon SK Kim SJ Lee HW Im DS Lee SS Ahn SK Kim SW Han CK Yoon JH Lee KJ Choi NS 《Bioorganic & medicinal chemistry letters》2008,18(23):6279-6282
In an effort to minimize side effects associated with low selectivity against PDE isozymes, we have successfully identified a series of 6,7,8-substituted quinzaolines as potent inhibitors of PDE5 with high level of isozyme selectivity, especially against PDE6 and PDE11. PDE5 potency and isozyme selectivity of quinazolines were greatly improved with substitutions both at 6- and 8-position. The synthesis, structure-activity relationships and in vivo efficacy of this novel series of potent PDE5 inhibitors are described. 相似文献
18.
Han YF Li CP Chow E Wang H Pang YP Carlier PR 《Bioorganic & medicinal chemistry》1999,7(11):2569-2575
Three series of 4-aminopyridine-and 4-aminoquinoline based symmetrical bivalent acetylcholinesterase (AChE) inhibitors were prepared and compared to previously synthesized dimers of 9-amino-1,2,3,4-tetrahydroacridine (tacrine). In each case significant, tether length-dependent increases in AChE inhibition potency and selectivity (up to 3000-fold) were observed relative to the corresponding monomer, indicating dual-site binding of these inhibitors to AChE. Assay of the corresponding alkylated monomers revealed that the alkylene tether played at least two complementary roles in the dimer series. In addition to reducing the entropy loss that occurs on binding both monomeric units of the dimer, the alkylene tether can also significantly improve potency through hydrophobic effects. 相似文献
19.
Hughes RO Maddux T Joseph Rogier D Lu S Walker JK Jon Jacobsen E Rumsey JM Zheng Y Macinnes A Bond BR Han S 《Bioorganic & medicinal chemistry letters》2011,21(21):6348-6352
We describe the design, synthesis and profiling of a novel series of PDE5 inhibitors. We take advantage of an alternate projection into the solvent region to identify compounds with excellent potency, selectivity and pharmacokinetic profiles. 相似文献
20.
《Bioorganic & medicinal chemistry letters》2020,30(22):127523
Hybridisation of amino-pyrimidine based SYK inhibitors (e.g. 1a) with previously reported diamine-based SYK inhibitors (e.g. TAK-659) led to the identification and optimisation of a novel pyrimidine-based series of potent and selective SYK inhibitors, where the original aminomethylene group was replaced by a 3,4-diaminotetrahydropyran group. The initial compound 5 achieved excellent SYK potency. However, it suffered from poor permeability and modest kinase selectivity. Further modifications of the 3,4-diaminotetrahydropyran group were identified and the interactions of those groups with Asp512 were characterised by protein X-ray crystallography. Further optimisation of this series saw mixed results where permeability and kinase selectivity were increased and oral bioavailability was achieved in the series, but at the expense of potent hERG inhibition. 相似文献