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1.
Jones CD Andrews DM Barker AJ Blades K Byth KF Finlay MR Geh C Green CP Johannsen M Walker M Weir HM 《Bioorganic & medicinal chemistry letters》2008,18(24):6486-6489
The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. The series was found to have much improved CDK2 inhibition and potent in vitro anti-proliferative effects against cancer cell lines. Control of overall lipophilicity was important to achieve good in vitro potency along with acceptable physiochemical properties and margins against inhibition of both CYP isoforms and the hERG potassium ion channel. A compound with an attractive overall balance of properties was profiled in vivo and possessed suitable physiochemical and pharmacokinetic profiles for oral dosing. 相似文献
2.
Brian N. Cook Jörg Bentzien Andre White Peter A. Nemoto Ji Wang Chuk C. Man Fariba Soleymanzadeh Hnin Hnin Khine Mohammed A. Kashem Stanley Z. Kugler John P. Wolak Gregory P. Roth Stéphane De Lombaert Steven S. Pullen Hidenori Takahashi 《Bioorganic & medicinal chemistry letters》2009,19(3):773-777
Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity. 相似文献
3.
Li H Tatlock J Linton A Gonzalez J Borchardt A Dragovich P Jewell T Prins T Zhou R Blazel J Parge H Love R Hickey M Doan C Shi S Duggal R Lewis C Fuhrman S 《Bioorganic & medicinal chemistry letters》2006,16(18):4834-4838
A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays. 相似文献
4.
Vijay Kumar D Hoarau C Bursavich M Slattum P Gerrish D Yager K Saunders M Shenderovich M Roth BL McKinnon R Chan A Cimbora DM Bradford C Reeves L Patton S Papac DI Williams BL Carlson RO 《Bioorganic & medicinal chemistry letters》2012,22(13):4377-4385
Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse. 相似文献
5.
Rajeev S. Bhide Alec Keon Carolyn Weigelt John S. Sack Robert J. Schmidt Shuqun Lin Hai-Yun Xiao Steven H. Spergel James Kempson William J. Pitts Julie Carman Michael A. Poss 《Bioorganic & medicinal chemistry letters》2017,27(21):4908-4913
The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay. 相似文献
6.
Design and synthesis of potent,orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase 总被引:3,自引:0,他引:3
Stelmach JE Liu L Patel SB Pivnichny JV Scapin G Singh S Hop CE Wang Z Strauss JR Cameron PM Nichols EA O'Keefe SJ O'Neill EA Schmatz DM Schwartz CD Thompson CM Zaller DM Doherty JB 《Bioorganic & medicinal chemistry letters》2003,13(2):277-280
The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h). 相似文献
7.
L’uboš Remeň Olivier Bezençon Sylvia Richard-Bildstein Daniel Bur Lars Prade Olivier Corminboeuf Christoph Boss Corinna Grisostomi Thierry Sifferlen Panja Strickner Patrick Hess Stéphane Delahaye Alexander Treiber Thomas Weller Christoph Binkert Beat Steiner Walter Fischli 《Bioorganic & medicinal chemistry letters》2009,19(23):6762-6765
New classes of de novo designed renin inhibitors are reported. Some of these compounds display excellent in vitro and in vivo activities toward human renin in a TGR model. The synthesis of these new types of mono- and bicyclic scaffolds are reported, and properties of selected compounds discussed. 相似文献
8.
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
9.
James E. Tarver Theodore C. Jessop Marianne Carlsen David J. Augeri Qinghong Fu Jason P. Healy Alexander Heim-Riether Amy Xu Jerry A. Taylor Min Shen Philip E. Keyes S. David Kimball Xuan-Chuan Yu Maricar Miranda Qingyun Liu Jonathan C. Swaffield Amr Nouraldeen Alan G.E. Wilson Rick Finch Kanchan Jhaver Kenneth G. Carson 《Bioorganic & medicinal chemistry letters》2009,19(23):6780-6783
A series of potent piperidine-linked cytosine derivatives were prepared as inhibitors of deoxycytidine kinase (dCK). Compound 9h was discovered to be a potent inhibitor of dCK and shows a good combination of cellular potency and pharmacokinetic parameters. Compound 9h blocks the incorporation of radiolabeled cytosine into mouse T-cells in vitro, as well as in vivo in mice following a T-cell challenge. 相似文献
10.
《Bioorganic & medicinal chemistry letters》2014,24(11):2525-2529
Heat shock protein 90 (HSP90) is a molecular chaperone to fold and maintain the proper conformation of many signaling proteins, especially some oncogenic proteins and mutated unstable proteins. Inhibition of HSP90 was recognized as an effective approach to simultaneously suppress several aberrant signaling pathways, and therefore it was considered as a novel target for cancer therapy. Here, by integrating several techniques including the fragment-based drug discovery method, fragment merging, computer aided inhibitor optimization, and structure-based drug design, we were able to identify a series of HSP90 inhibitors. Among them, inhibitors 13, 32, 36 and 40 can inhibit HSP90 with IC50 about 20–40 nM, which is at least 200-fold more potent than initial fragments in the protein binding assay. These new HSP90 inhibitors not only explore interactions with an under-studied subpocket, also offer new chemotypes for the development of novel HSP90 inhibitors as anticancer drugs. 相似文献
11.
McLean LR Zhang Y Zaidi N Bi X Wang R Dharanipragada R Jurcak JG Gillespy TA Zhao Z Musick KY Choi YM Barrague M Peppard J Smicker M Duguid M Parkar A Fordham J Kominos D 《Bioorganic & medicinal chemistry letters》2012,22(9):3296-3300
Beginning with a screening hit, unique thienopyrazole-indole inhibitors of Itk (interleukin-2-inducible tyrosine kinase) were designed, synthesized, and crystallized in the target kinase. Although initial compounds were highly active in Itk, they were not selective. Increasing the steric bulk around a tertiary alcohol at the 5-indole position dramatically improved selectivity toward Lyk and Syk, but not Txk. Substitutions at the 3- and 4-indole positions gave less active compounds that remained poorly selective. A difluoromethyl substitution at the 5-position of the thienopyrazole led to a highly potent and selective compound. Phenyl at this position reduced activity and selectivity while pushing the side-chains of Lys-391 and Asp-500 away from the binding pocket. Novel and selective thienopyrazole inhibitors of Itk were designed as a result of combining structure-based design and medicinal chemistry. 相似文献
12.
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
13.
Sisir Nandi 《Molecular simulation》2013,39(3):196-209
This paper is an attempt to design 4-anilinoquinazoline compounds having promising anticancer activities against epidermal growth factor (EGFR) kinase inhibition, using virtual combinatorial library approach. Partial least squares method has been applied for the development of a quantitative structure–activity relationship (QSAR) model based on training and test set approaches. The partial least squares model showed some interesting results in terms of internal and external predictability against EGFR kinase inhibition for such type of anilinoquinazoline derivatives. In virtual screening study, out of 4860 compounds in chemical library, 158 compounds were screened and finally, 10 compounds were selected as promising EGFR kinase inhibitors based on their predicted activities from the QSAR model. These derivatives were subjected to molecular docking study to investigate the mode of binding with the EGFR kinase, and the two compounds (ID 3639 and 3399) showing similar type of docking score and binding patterns with that of the existing drug molecules like erlotinib were finally reported. 相似文献
14.
Coburn CA Rush DM Williams PD Homnick C Lyle EA Lewis SD Lucas BJ Di Muzio-Mower JM Juliano M Krueger JA Vastag K Chen IW Vacca JP 《Bioorganic & medicinal chemistry letters》2000,10(10):1069-1072
A new class of conformationally constrained thrombin inhibitors is described. These compounds contain a unique bicyclic pyridone scaffold which serves as a P3P2 dipeptide surrogate. The synthesis and antithrombotic activity of these inhibitors is reported. 相似文献
15.
Lu Z Bohn J Rano T Rutkowski CA Simcoe AL Olsen DB Schleif WA Carella A Gabryelski L Jin L Lin JH Emini E Chapman K Tata JR 《Bioorganic & medicinal chemistry letters》2005,15(23):5311-5314
Efforts directed to identifying potent HIV protease inhibitors (PI) have yielded a class of compounds that are not only very active against wild-type (NL4-3) HIV virus but also very potent against a panel of PI-resistant viral isolates. Chemistry and biology are described. 相似文献
16.
Chandrasekaran Meganathan Sugunadevi Sakkiah Yuno Lee Jayavelu Venkat Narayanan Keun Woo Lee 《Journal of molecular modeling》2013,19(2):715-726
In our study, a structure-based virtual screening study was conducted to identify potent ITK inhibitors, as ITK is considered to play an important role in the treatment of inflammatory diseases. We developed a structure-based pharmacophore model using the crystal structure (PDB ID: 3MJ2) of ITK complexed with BMS-50944. The most predictive model, SB-Hypo1, consisted of six features: three hydrogen-bond acceptors (HBA), one hydrogen-bond donor (HBD), one ring aromatic (RA), and one hydrophobic (HY). The statistical significance of SB-Hypo1 was validated using wide range of test set molecules and a decoy set. The resulting well-validated model could then be confidently used as a 3D query to screen for drug-like molecules in a database, in order to retrieve new chemical scaffolds that may be potent ITK inhibitors. The hits retrieved from this search were filtered based on the maximum fit value, drug-likeness, and ADMET properties, and the hits that were retained were used in a molecular docking study to find the binding mode and molecular interactions with crucial residues at the active site of the protein. These hits were then fed into a molecular dynamics simulation to study the flexibility of the activation loop of ITK upon ligand binding. This combination of methodologies is a valuable tool for identifying structurally diverse molecules with desired biological activities, and for designing new classes of selective ITK inhibitors. Figure
A structure-based pharmacophore model was developed, using a fully resolved crystal structure, in order to identify novel virtual lead compounds for use in ITK inhibitor design 相似文献
17.
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
18.
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
19.
Hans Matter Gerhard Zoller Andreas W. Herling Juan-Antonio Sanchez-Arias Christophe Philippo Claudie Namane Markus Kohlmann Anja Pfenninger Marc D. Voss 《Bioorganic & medicinal chemistry letters》2013,23(6):1817-1822
The discovery of potent benzimidazole stearoyl-CoA desaturase (SCD1) inhibitors by ligand-based virtual screening is described. ROCS 3D-searching gave a favorable chemical motif that was subsequently optimized to arrive at a chemical series of potent and promising SCD1 inhibitors. In particular, compound SAR224 was selected for further pharmacological profiling based on favorable in vitro data. After oral administration to male ZDF rats, this compound significantly decreased the serum fatty acid desaturation index, thus providing conclusive evidence for SCD1 inhibition in vivo by SAR224. 相似文献
20.
Helen V. Waldschmidt Renee Bouley Paul D. Kirchhoff Pil Lee John J.G. Tesmer Scott D. Larsen 《Bioorganic & medicinal chemistry letters》2018,28(9):1507-1515
G protein-coupled receptor (GPCR) kinases (GRKs) regulate the desensitization and internalization of GPCRs. Two of these, GRK2 and GRK5, are upregulated in heart failure and are promising targets for heart failure treatment. Although there have been several reports of potent and selective inhibitors of GRK2 there are few for GRK5. Herein, we describe a ligand docking approach utilizing the crystal structures of the GRK2–Gβγ·GSK180736A and GRK5·CCG215022 complexes to search for amide substituents predicted to confer GRK2 and/or GRK5 potency and selectivity. From this campaign, we successfully generated two new potent GRK5 inhibitors, although neither exhibited selectivity over GRK2. 相似文献