共查询到20条相似文献,搜索用时 15 毫秒
1.
Levin JI Chen J Du M Hogan M Kincaid S Nelson FC Venkatesan AM Wehr T Zask A DiJoseph J Killar LM Skala S Sung A Sharr M Roth C Jin G Cowling R Mohler KM Black RA March CJ Skotnicki JS 《Bioorganic & medicinal chemistry letters》2001,11(16):2189-2192
A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p. 相似文献
2.
J I Levin J M Chen M T Du F C Nelson T Wehr J F DiJoseph L M Killar S Skala A Sung M A Sharr C E Roth G Jin R Cowling L Di M Sherman Z B Xu C J March K M Mohler R A Black J S Skotnicki 《Bioorganic & medicinal chemistry letters》2001,11(22):2975-2978
Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13. 相似文献
3.
Boyer SJ Burke J Guo X Kirrane TM Snow RJ Zhang Y Sarko C Soleymanzadeh L Swinamer A Westbrook J Dicapua F Padyana A Cogan D Gao A Xiong Z Madwed JB Kashem M Kugler S O'Neill MM 《Bioorganic & medicinal chemistry letters》2012,22(1):733-737
A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were identified through high throughput screening. An RSK crystal structure and exploratory SAR were used to define the series pharmacophore. Compounds with good cell potency, such as compounds 43, 44, and 55 were identified, and form the basis for subsequent kinase selectivity optimization. 相似文献
4.
《Bioorganic & medicinal chemistry letters》1999,9(1):1-6
Eight small molecules were synthesized to evaluate the structure activity relationships (SAR) of N-substituted anthranilic acids. The molecules were synthesized by benzylation or arylation of methyl anthranilate. A light scattering-based amyloid fibril formation assay was used to evaluate potential inhibitors of transthyretin (TTR) amyloid fibril formation in vitro. The m-carboxyphenylated and o-trifluoromethylphenylated anthranilic acids are potent inhibitors that will be subjected to further SAR and structural analysis. 相似文献
5.
Mizuno K Sawa M Harada H Tateishi H Oue M Tsujiuchi H Furutani Y Kato S 《Bioorganic & medicinal chemistry letters》2004,14(24):5959-5962
A series of tryptamine-based 2-thiophenesulfonamide derivatives were prepared and their agonistic activity for the beta-adrenergic receptors (ARs) was evaluated. Compound 54, containing 7-methanesulfonyloxy tryptamine, was found to be a highly potent beta3-AR agonist (EC50=0.21 nM, IA=97%) with excellent selectivity for the beta3-AR over the beta1- and beta2-ARs (210- and 86-fold, respectively). 相似文献
6.
Finke PE Meurer LC Levorse DA Mills SG Maccoss M Sadowski S Cascieri MA Tsao KL Chicchi GG Metzger JM Macintyre DE 《Bioorganic & medicinal chemistry letters》2006,16(17):4497-4503
An initial investigation of the novel cyclopentane scaffold 6 afforded low nanomolar human NK1 antagonists having enhanced water solubility properties compared to morpholine 1. A synthesis of this cyclopentane scaffold, having three contiguous chiral centers, and the unexpected determination that the 1,2-trans-2,3-trans-ring stereochemistry, as opposed to the cis-ether/phenyl configuration of the known structures 1-5, is optimal for this class of antagonist are described. 相似文献
7.
《Bioorganic & medicinal chemistry letters》2001,11(15):1975-1979
A series of carboxylic acids was prepared based on cyclohexylglycine scaffolds and tested for potency as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors such as compound 18 display low nanomolar potency for MMP-2 and MMP-13, while selectively sparing MMP-1 and MMP-7. 相似文献
8.
Siu T Kozina ES Jung J Rosenstein C Mathur A Altman MD Chan G Xu L Bachman E Mo JR Bouthillette M Rush T Dinsmore CJ Marshall CG Young JR 《Bioorganic & medicinal chemistry letters》2010,20(24):7421-7425
This paper describes the discovery and design of a novel class of JAK2 inhibitors. Furthermore, we detail the optimization of a screening hit using ligand binding efficiency and log D. These efforts led to the identification of compound 41, which demonstrates in vivo activity in our study. 相似文献
9.
Kohrt JT Filipski KJ Cody WL Bigge CF La F Welch K Dahring T Bryant JW Leonard D Bolton G Narasimhan L Zhang E Peterson JT Haarer S Sahasrabudhe V Janiczek N Desiraju S Hena M Fiakpui C Saraswat N Sharma R Sun S Maiti SN Leadley R Edmunds JJ 《Bioorganic & medicinal chemistry》2006,14(13):4379-4392
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability. 相似文献
10.
Levin JI Chen JM Cheung K Cole D Crago C Santos ED Du X Khafizova G MacEwan G Niu C Salaski EJ Zask A Cummons T Sung A Xu J Zhang Y Xu W Ayral-Kaloustian S Jin G Cowling R Barone D Mohler KM Black RA Skotnicki JS 《Bioorganic & medicinal chemistry letters》2003,13(16):2799-2803
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors, all bearing a butynyloxy P1' group, was explored. In particular, compound 5j has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and MMP-9, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model. 相似文献
11.
Levy DE Wang DX Lu Q Chen Z Perumattam J Xu YJ Liclican A Higaki J Dong H Laney M Mavunkel B Dugar S 《Bioorganic & medicinal chemistry letters》2008,18(7):2390-2394
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 34nM to >20microM and were dependant upon both the nature of the aryl group and the hydrogen bond donating potential of the maleimide ring. Key interactions with the kinase ATP site and hinge region were found to be consistent with homology modeling predictions. 相似文献
12.
Ingo V. Hartung Marion Hitchcock Florian Pühler Roland Neuhaus Arne Scholz Stefanie Hammer Kirstin Petersen Gerhard Siemeister Dominic Brittain Roman C. Hillig 《Bioorganic & medicinal chemistry letters》2013,23(8):2384-2390
Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed—despite being orally bioavailable and not a P-glycoprotein substrate—much lower brain/plasma exposure ratios than PD325901. 相似文献
13.
A quantitative structure-activity relationship (QSAR) study has been made on four different series of anthranilic acid-based matrix metalloproteinase (MMP) inhibitors, in which two substituted aryl rings, one bearing the hydroxamic acid moiety that binds with the zinc atom of MMPs, are joined through a bridge group of sulfonamide. The QSAR results indicate that the sulfonamide group plays a very important role in the inhibition activity of the inhibitors and that the effectiveness of this sulfonamide group can be increased by the presence at the aryl rings or at the sulfonamide nitrogen itself of nitrogen-containing or some such substituents that can increase the electronic character of the sulfonamide group. The hydrophobic character of the molecules is not found to be of any advantage; rather in most of the cases it is shown to have detrimental effect, suggesting that MMPs provide little opportunity to the inhibitors to have a any hydrophobic interactions with them. On the other hand, polarizability of the molecules has been found to be conducive to activity in some cases. Thus the inhibition mechanism seems to predominantly involve the electronic interactions between the inhibitors and the enzymes. 相似文献
14.
Yin Z Patel SJ Wang WL Chan WL Ranga Rao KR Wang G Ngew X Patel V Beer D Knox JE Ma NL Ehrhardt C Lim SP Vasudevan SG Keller TH 《Bioorganic & medicinal chemistry letters》2006,16(1):40-43
With the aim of discovering potent and selective dengue NS3 protease inhibitors, we systematically synthesized and evaluated a series of tetrapeptide aldehydes based on lead aldehyde 1 (Bz-Nle-Lys-Arg-Arg-H, K(i)=5.8 microM). In general, we observe that interactions of P(2) side chain are more important than P(1) followed by P(3) and P(4). Tripeptide and dipeptide aldehyde inhibitors also show low micromolar activity. Additionally, an effective non-basic, uncharged replacement of P(1) Arg is identified. 相似文献
15.
Levin JI Chen JM Du MT Nelson FC Killar LM Skala S Sung A Jin G Cowling R Barone D March CJ Mohler KM Black RA Skotnicki JS 《Bioorganic & medicinal chemistry letters》2002,12(8):1199-1202
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production. 相似文献
16.
Provins L Christophe B Danhaive P Dulieu J Gillard M Quéré L Stebbins K 《Bioorganic & medicinal chemistry letters》2007,17(11):3077-3080
Introduction of 3-substituted azetidinyl substituents onto the 4,6-diaminopyrimidine scaffold allowed the improvement of PDE4 inhibiting activities. Preliminary in vivo activity in pulmonary inflammation models is reported. 相似文献
17.
Lindsley CW Zhao Z Leister WH Robinson RG Barnett SF Defeo-Jones D Jones RE Hartman GD Huff JR Huber HE Duggan ME 《Bioorganic & medicinal chemistry letters》2005,15(3):761-764
This letter describes the development of two series of potent and selective allosteric Akt kinase inhibitors that display an unprecedented level of selectivity for either Akt1, Akt2 or both Akt1/Akt2. An iterative analog library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo. 相似文献
18.
Chen HY Kim S Wu JY Birzin ET Chan W Yang YT Dahllund J DiNinno F Rohrer SP Schaeffer JM Hammond ML 《Bioorganic & medicinal chemistry letters》2004,14(10):2551-2554
A series of 3-alkyl, 3-cycloalkyl, and 3-heteroaryl dihydrobenzoxathiin analogs 1 were prepared and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. In general, the compounds were found to exhibit a high degree of selectivity for ER alpha over ER beta, but were less potent than the original lead compound 1a in the inhibition of estradiol-driven uterine proliferation. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(6):1466-1471
This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor–water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity. 相似文献
20.
Stiff C Graber DR Thorarensen A Wakefield BD Marotti KR Melchior EP Sweeney MT Han F Rohrer DC Zurenko GE Romero DL 《Bioorganic & medicinal chemistry letters》2008,18(23):6293-6297
The discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents has been described in a recent series of papers. This paper describes the discovery of 1-acylindazol-3-ols as a novel bioisostere of an anthranilic acid. The synthesis and structure-activity relationships of the indazol bioisosteres are described herein. 相似文献