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1.
Condon JS Joseph-McCarthy D Levin JI Lombart HG Lovering FE Sun L Wang W Xu W Zhang Y 《Bioorganic & medicinal chemistry letters》2007,17(1):34-39
By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14. 相似文献
2.
Reverse hydroxamate-based selective TACE inhibitors 总被引:1,自引:0,他引:1
Kamei N Tanaka T Kawai K Miyawaki K Okuyama A Murakami Y Arakawa Y Haino M Harada T Shimano M 《Bioorganic & medicinal chemistry letters》2004,14(11):2897-2900
Reverse hydroxamate-based selective TACE inhibitors are described. They have potent TACE inhibitory activities and excellent selectivities against MMP-1, 2, 3, 8, 9, 13, 14, and 17. One representative compound, 18 has demonstrated an excellent oral inhibitory activity of the lipopolysaccharide (LPS)-stimulated TNF-alpha production in rats. 相似文献
3.
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
4.
Zask A Kaplan J Du X MacEwan G Sandanayaka V Eudy N Levin J Jin G Xu J Cummons T Barone D Ayral-Kaloustian S Skotnicki J 《Bioorganic & medicinal chemistry letters》2005,15(6):1641-1645
Potent and selective TACE and MMP inhibitors utilizing the diazepine and thiazepine ring systems were synthesized and evaluated for biological activity in in vitro and in vivo models of TNF-alpha release. Oral activity in the mouse LPS model of TNF-alpha release was seen. Efficacy in the mouse collagen induced arthritis model was achieved with diazepine 20. 相似文献
5.
Zask A Gu Y Albright JD Du X Hogan M Levin JI Chen JM Killar LM Sung A DiJoseph JF Sharr MA Roth CE Skala S Jin G Cowling R Mohler KM Barone D Black R March C Skotnicki JS 《Bioorganic & medicinal chemistry letters》2003,13(8):1487-1490
Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis. 相似文献
6.
Tsukida T Moriyama H Inoue Y Kondo H Yoshino K Nishimura S 《Bioorganic & medicinal chemistry letters》2004,14(6):1569-1572
A series of azasugar-based hydroxamic acid derivatives bearing 2R,3R,4R,5R-configuration is described. Compound 4c with 4,5-O-acetonide group showed excellent in vitro potency against TACE, with high selectivity over MMP-1 and moderate selectivity over MMP-3 and MMP-9. 相似文献
7.
Cywin CL Dahmann G Prokopowicz AS Young ER Magolda RL Cardozo MG Cogan DA Disalvo D Ginn JD Kashem MA Wolak JP Homon CA Farrell TM Grbic H Hu H Kaplita PV Liu LH Spero DM Jeanfavre DD O'Shea KM White DM Woska JR Brown ML 《Bioorganic & medicinal chemistry letters》2007,17(1):225-230
An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds. 相似文献
8.
Becker DP DeCrescenzo G Freskos J Getman DP Hockerman SL Li M Mehta P Munie GE Swearingen C 《Bioorganic & medicinal chemistry letters》2001,11(20):2723-2725
A series of alpha-alkyl-alpha-amino-beta-sulphone hydroxamates was prepared and evaluated for potency versus MMP-2 and MMP-13, and for selectivity versus MMP-1. Low nanomolar potency was obtained with selectivity versus MMP-1 ranging from >10 to >1000. Selected compounds were orally bioavailable. 相似文献
9.
Subramaniam R Haldar MK Tobwala S Ganguly B Srivastava DK Mallik S 《Bioorganic & medicinal chemistry letters》2008,18(11):3333-3337
A series of bis-(arylsulfonamide) hydroxamate inhibitors were synthesized. These compounds exhibit good potency against MMP-7 and MMP-9 depending on the nature, steric bulk, and substitution pattern of the substituents in the benzene ring. In general, the preliminary structure-activity relationships (SAR) suggest that among the DAPA hydroxamates (i) electron-rich benzene rings of the sulfonamides may produce better inhibitors than electron-poor analogs. However, potential H-bond acceptors can reverse the trend depending on the isozyme; (ii) isozyme selectivity between MMP-7 and -9 can be conferred through steric bulk and substitution pattern of the substituents in the benzene ring, and (iii) the MMP-10 inhibition pattern of the compounds paralleled that for MMP-9. 相似文献
10.
The 5,5-disubstitutedpyrimidine-2,4,6-triones represent a new class of MMP inhibitors showing selectivity for the gelatinases A and B, collagenase-3, and human neutrophil collagenase. The SAR presented here is in good agreement with an X-ray structure of compound 5 bound to the catalytic domain of stromelysin-1. While of the barbiturate structural class, compound 5 did not show any toxic or sedative effects. 相似文献
11.
《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
12.
McDonald O Lackey K Davis-Ward R Wood E Samano V Maloney P Deanda F Hunter R 《Bioorganic & medicinal chemistry letters》2006,16(20):5378-5383
The synthesis of several novel aza-stilbene derivatives was carried out. The compounds were tested for their c-RAF enzyme inhibition. Compound 27 possesses significant potency against c-RAF and demonstrates selectivity over other protein kinases. A hypothesis for the binding mode, activity, and selectivity is proposed. 相似文献
13.
Janser P Neumann U Miltz W Feifel R Buhl T 《Bioorganic & medicinal chemistry letters》2006,16(10):2632-2636
The structural features contributing to the different pharmacokinetic properties of the TACE/MMP inhibitors TNF484 and Trocade were analyzed using an in vivo cassette-dosing approach in rats. This enabled us to identify a new lead compound with excellent pharmacokinetic properties, but weaker activity on the biological targets. Directed structural modifications maintained oral bioavailability and restored biological activity, leading to a novel compound almost equipotent to TNF484 in vivo, but with a more than tenfold higher oral bioavailability. 相似文献
14.
J N Freskos J J McDonald B V Mischke P B Mullins H S Shieh R A Stegeman A M Stevens 《Bioorganic & medicinal chemistry letters》1999,9(13):1757-1760
We have discovered a new series of potent conformationally constrained MMP Inhibitors that are selective for MMP-13 over MMP-1. 相似文献
15.
Wu J Rush TS Hotchandani R Du X Geck M Collins E Xu ZB Skotnicki J Levin JI Lovering FE 《Bioorganic & medicinal chemistry letters》2005,15(18):4105-4109
A potent, selective series of MMP-13 inhibitors has been derived from a weak (3.2 microM) inhibitor that did not bear a zinc chelator. Structure-based drug design strategies were employed to append a Zn-chelating group to one end of the molecule and functionality to enhance selectivity to the other. A compound from this series demonstrated rat oral bioavailability and efficacy in a bovine articular cartilage explant model. 相似文献
16.
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
17.
Matrix Metalloproteinase are family of enzymes responsible for degradation of extracellular matrix. MMP9 (gelatinase B) is one of the common matrix metalloproteinase that is associated with tissue destruction in a number of disease states such as rheumatoid arthiritis, fibrotic lung disease, dilated cardiomyopathy, as well as cancer invasion and metastasis. Recent study demonstrates that increased expression of MMP9 results in augmentation of myopathy with increased inflammation and fibernecrosis. Previous studies do not provide any conclusive information related to structural specificity of MMP9 inhibitors towards its active site, but with the availability of experimental structures it is now possible to study the structural specificity of MMP9 inhibitors. In light of availability of this information, we have applied docking and molecular dynamics approach to study the binding of inhibitors to the active site of MMP9. Three categories of inhibitor consisting of sulfonamide hydroxamate, thioester, and carboxylic moieties as zinc binding groups (ZBG) were chosen in the present study. Our docking results demonstrate that thioester based zinc binding group gives favourable docking scores as compared to other two groups. Molecular Dynamics simulations further reveal that tight binding conformation for thioester group has high specificity for MMP9 active site. Our study provides valuable insights on inhibitor specificity of MMP9 which provides valuable hints for future design of potent inhibitors and drugs. 相似文献
18.
Durón SG Lindstrom A Bonnefous C Zhang H Chen X Symons KT Sablad M Rozenkrants N Zhang Y Wang L Yazdani N Shiau AK Noble SA Rix P Rao TS Hassig CA Smith ND 《Bioorganic & medicinal chemistry letters》2012,22(2):1237-1241
The overproduction of nitric oxide during the biological response to inflammation by the nitric oxide synthase (NOS) enzymes have been implicated in the pathology of many diseases. By removal of the amide core from uHTS-derived quinolone 4, a new series highly potent heteroaromatic-aminomethyl quinolone iNOS inhibitors 8 were identified. SAR studies led to identification of piperazine 22 and pyrimidine 32, both of which reduced plasma nitrates following oral dosing in a mouse lipopolysaccharide challenge assay. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(4):1116-1121
We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition. 相似文献
20.
Barta TE Becker DP Bedell LJ De Crescenzo GA McDonald JJ Munie GE Rao S Shieh HS Stegeman R Stevens AM Villamil CI 《Bioorganic & medicinal chemistry letters》2000,10(24):2815-2817
A series of novel, MMP-1 sparing arylhydroxamate sulfonamides with activity against MMP-2 and -13 is described. 相似文献