共查询到20条相似文献,搜索用时 15 毫秒
1.
Mortensen DS Perrin-Ninkovic SM Harris R Lee BG Shevlin G Hickman M Khambatta G Bisonette RR Fultz KE Sankar S 《Bioorganic & medicinal chemistry letters》2011,21(22):6793-6799
We report here the discovery of a novel series of selective mTOR kinase inhibitors. A series of imidazo[4,5-b]pyrazin-2-ones, represented by screening hit 1, was developed into lead compounds with excellent mTOR potency and exquisite kinase selectivity. Potent compounds from this series show >1000-fold selectivity over the related PI3Kα lipid kinase. Further, compounds such as 2 achieve mTOR pathway inhibition, blocking both mTORC1 and mTORC2 signaling, in PC3 cancer cells as measured by inhibition of pS6 and pAkt (S473). 相似文献
2.
McClellan WJ Dai Y Abad-Zapatero C Albert DH Bouska JJ Glaser KB Magoc TJ Marcotte PA Osterling DJ Stewart KD Davidsen SK Michaelides MR 《Bioorganic & medicinal chemistry letters》2011,21(18):5620-5624
In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrimidine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors. 相似文献
3.
Rahman SS Coulton S Herdon HJ Joiner GF Jin J Porter RA 《Bioorganic & medicinal chemistry letters》2007,17(6):1741-1745
High throughput screening led to the discovery of a novel series of 1,3-diaminopropan-2-ol sulfonamides as selective GlyT-1 inhibitors. Structure-activity relationships of this novel series and optimisation of the initial hit that led to the identification of (2), a potent and selective GlyT-1 inhibitor, are also presented. 相似文献
4.
Joshua Kaplan Jeroen C. Verheijen Natasja Brooijmans Lourdes Toral-Barza Irwin Hollander Ker Yu Arie Zask 《Bioorganic & medicinal chemistry letters》2010,20(2):640-643
The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. These results establish the DHP group as a hinge-region binding motif for the preparation of highly potent and selective mTOR inhibitors. 相似文献
5.
Lowe J Drozda S Qian W Peakman MC Liu J Gibbs J Harms J Schmidt C Fisher K Strick C Schmidt A Vanase M Lebel L 《Bioorganic & medicinal chemistry letters》2007,17(6):1675-1678
The synthesis and structure-activity relationships (SAR) of a series of indane and tetralin inhibitors of the type 1 glycine transporter, derived from a high-throughput screening (HTS) hit, are described. Key modifications that reduced the 5HT1B receptor affinity of the HTS hit and the P450 2D6 inhibition of subsequent analogues are delineated. While these modifications led to potent and selective GlyT1 inhibitors, HERG affinity and human microsomal clearance remain an issue for this series of compounds. 相似文献
6.
Caldarelli M Angiolini M Disingrini T Donati D Guanci M Nuvoloni S Posteri H Quartieri F Silvagni M Colombo R 《Bioorganic & medicinal chemistry letters》2011,21(15):4507-4511
The synthesis and SAR of a series of novel pyrazolo-quinazolines as potent and selective MPS1 inhibitors are reported. We describe the optimization of the initial hit, identified by screening the internal library collection, into an orally available, potent and selective MPS1 inhibitor. 相似文献
7.
Wallace MB Feng J Zhang Z Skene RJ Shi L Caster CL Kassel DB Xu R Gwaltney SL 《Bioorganic & medicinal chemistry letters》2008,18(7):2362-2367
A novel series of non-covalent, benzimidazole-based inhibitors of DPP-4 has been developed from a small fragment hit using structure-based drug design. A highly versatile synthetic route was created for the development of SAR, which led to the discovery of potent and selective inhibitors with excellent pharmaceutical properties. 相似文献
8.
Theodore C. Jessop James E. Tarver Marianne Carlsen Amy Xu Jason P. Healy Alexander Heim-Riether Qinghong Fu Jerry A. Taylor David J. Augeri Min Shen Terry R. Stouch Ronald V. Swanson Leslie W. Tari Michael Hunter Isaac Hoffman Philip E. Keyes Xuan-Chuan Yu Maricar Miranda Qingyun Liu Jonathan C. Swaffield Kenneth G. Carson 《Bioorganic & medicinal chemistry letters》2009,19(23):6784-6787
A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo. 相似文献
9.
David J. Richard Jeroen C. Verheijen Kevin Curran Joshua Kaplan Lourdes Toral-Barza Irwin Hollander Judy Lucas Ker Yu Arie Zask 《Bioorganic & medicinal chemistry letters》2009,19(24):6830-6835
A series of highly potent and selective pyrazolopyrimidine mTOR inhibitors which contain water-solubilizing groups attached to the 6-arylureidophenyl moiety have been prepared. Such derivatives displayed superior potency to those in which these appendages were attached to alternative sites. In comparison to unfunctionalized arylureido compounds, these analogs demonstrated enhanced cellular potency and significantly improved stability towards human microsomes, resulting in an mTOR inhibitor with impressive efficacy in a xenograft model with an intermittent dosing regimen. 相似文献
10.
Xingchun Han Min Jiang Chengang Zhou Zheng Zhou Zhiheng Xu Lisha Wang Alexander V. Mayweg Rui Niu Tai-Guang Jin Song Yang 《Bioorganic & medicinal chemistry letters》2017,27(18):4488-4492
A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability. 相似文献
11.
Discovery of potent,selective and orally bioavailable imidazo[1,5-a]pyrazine derived ACK1 inhibitors
Meizhong Jin Jing Wang Andrew Kleinberg Mridula Kadalbajoo Kam W. Siu Andrew Cooke Mark A. Bittner Yan Yao April Thelemann Qunsheng Ji Shripad Bhagwat Kristen M. Mulvihill Josef A. Rechka Jonathan A. Pachter Andrew P. Crew David Epstein Mark J. Mulvihill 《Bioorganic & medicinal chemistry letters》2013,23(4):979-984
This Letter describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent exploration of structure–activity relationships and optimization of drug metabolism and pharmacokinetic properties led to the identification of potent, selective and orally bioavailable ACK1 inhibitors. 相似文献
12.
Hairuo Peng Doeg-Il Kim Jann N Sarkaria Yong-Seo Cho Robert T Abraham Leon H Zalkow 《Bioorganic & medicinal chemistry》2002,10(1):167-174
Several pyrrolo-quinoline gamma-lactones were found as novel inhibitors for two members of the PI3-kinase related kinase (PIKK) family, Ataxia-Telangiectasia-mutated (ATM) protein and the mammalian Target of Rapamycin (mTOR). Preliminary structure-activity relationship studies indicated that an electrophilic exocyclic double bond conjugated to the carbonyl group of the gamma-lactone ring was crucial for the PIKK inhibitory potency. One of the best ATM inhibitors in this series, DK8G557, showed IC(50) values of 0.6 and 7.0 microM for ATM and mTOR, respectively. This compound exhibited potent and selective growth inhibition activities in the NCI 60 human tumor cell line screen with a GI(50) MG-MID value of 2.69 microM. The best mTOR inhibitor in this series, HP9912, exhibited IC(50) values of 0.5 and 6.5 microM for mTOR and ATM, respectively. These compounds suggest novel leads for the discovery of potent small molecule inhibitors of PIKKs as potential anticancer drugs, with therapeutic activities as either single, or as sensitizing agents to conventional radio-, or chemo-therapeutic strategies. 相似文献
13.
《Bioorganic & medicinal chemistry letters》2019,29(21):126659
Aided by Structure Based Drug Discovery (SBDD), we rapidly designed a highly novel and selective series of mTOR inhibitors. This chemotype conveys exquisite kinase selectivity, excellent in vitro and in vivo potencies and ADME safety profiles. These compounds could serve as good tools to explore the potential of TORC inhibition in various human diseases. 相似文献
14.
Backes BJ Longenecker K Hamilton GL Stewart K Lai C Kopecka H von Geldern TW Madar DJ Pei Z Lubben TH Zinker BA Tian Z Ballaron SJ Stashko MA Mika AK Beno DW Kempf-Grote AJ Black-Schaefer C Sham HL Trevillyan JM 《Bioorganic & medicinal chemistry letters》2007,17(7):2005-2012
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal. 相似文献
15.
Dominique Lesuisse Gilles Dutruc-Rosset Gilles Tiraboschi Matthias K. Dreyer Sébastien Maignan Alain Chevalier Frank Halley Philippe Bertrand Marie-Claude Burgevin Dominique Quarteronet Thomas Rooney 《Bioorganic & medicinal chemistry letters》2010,20(6):1985-1989
From an HTS hit, a series of potent and selective inhibitors of GSK3β have been designed based on a Cdk2-homology model and with the help of several crystal structures of the compounds within Cdk2. 相似文献
16.
Timothy Forsyth Patrick C. Kearney Byung Gyu Kim Henry W.B. Johnson Naing Aay Arlyn Arcalas David S. Brown Vicky Chan Jeff Chen Hongwang Du Sergey Epshteyn Adam A. Galan Tai P. Huynh Mohamed A. Ibrahim Brian Kane Elena S. Koltun Grace Mann Lisa E. Meyr Matthew S. Lee Gary L. Lewis Peiwen Yu 《Bioorganic & medicinal chemistry letters》2012,22(24):7653-7658
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials. 相似文献
17.
Mammalian target of rapamycin (mTOR) is a protein kinase that controls cell growth, proliferation, and survival. mTOR signaling is often upregulated in cancer and there is great interest in developing drugs that target this enzyme. Rapamycin and its analogs bind to a domain separate from the catalytic site to block a subset of mTOR functions. These drugs are extremely selective for mTOR and are already in clinical use for treating cancers, but they could potentially activate an mTOR-dependent survival pathway that could lead to treatment failure. By contrast, small molecules that compete with ATP in the catalytic site would inhibit all of the kinase-dependent functions of mTOR without activating the survival pathway. Several non-selective mTOR kinase inhibitors have been described and here we review their chemical and cellular properties. Further development of selective mTOR kinase inhibitors holds the promise of yielding potent anticancer drugs with a novel mechanism of action. 相似文献
18.
Bolin Geng Gregory Basarab Janelle Comita-Prevoir Madhusudhan Gowravaram Pamela Hill Andrew Kiely James Loch Lawrence MacPherson Marshall Morningstar George Mullen Ekundayo Osimboni Alexander Satz Charles Eyermann Tomas Lundqvist 《Bioorganic & medicinal chemistry letters》2009,19(3):930-936
An SAR study of an HTS screening hit generated a series of pyridodiazepine amines as potent inhibitors of Helicobacter pylori glutamate racemase (MurI) showing highly selective anti-H. pylori activity, marked improved solubility, and reduced plasma protein binding. X-ray co-crystal E–I structures were obtained. These uncompetitive inhibitors bind at the MurI dimer interface. 相似文献
19.
Poulsen A Williams M Nagaraj HM William AD Wang H Soh CK Xiong ZC Dymock B 《Bioorganic & medicinal chemistry letters》2012,22(2):1009-1013
A virtual screen of our in-house database using various fingerprint techniques returned several triazine hits which were found to be mTOR inhibitors with a slight selectivity over PI3Kα. Using structure-guided lead optimization the inhibitory activity towards mTOR and PI3Kα was increased to the low nanomolar range. Exploiting shape differences in the binding-site allowed for the design of mTOR selective inhibitors. Focus on ligand efficiency ensured the inhibitors retained a low molecular weight and desirable drug-like properties. 相似文献
20.
Chiasson JF Boulet L Brideau C Chau A Claveau D Côté B Ethier D Giroux A Guay J Guiral S Mancini J Massé F Méthot N Riendeau D Roy P Rubin J Xu D Yu H Ducharme Y Friesen RW 《Bioorganic & medicinal chemistry letters》2011,21(5):1488-1492
A novel series of trisubstituted ureas has been identified as potent and selective mPGES-1 inhibitors. These compounds are selective over other prostanoid enzymes such as PGF synthase and TX synthase. This series of inhibitors was developed by lead optimization of a hit from an internal HTS campaign. Lead compound 42 is potent in A549 cell assay (IC50 of 0.34 μM) and in human whole blood assay (IC50 of 2.1 μM). An efficient and versatile one-pot strategy for the formation of ureas, involving a reductive amination, was developed to generate these inhibitors. 相似文献