共查询到20条相似文献,搜索用时 31 毫秒
1.
Hemaka A. Rajapakse Philippe G. Nantermet Harold G. Selnick James C. Barrow Georgia B. McGaughey Sanjeev Munshi Stacey R. Lindsley Mary Beth Young Phung L. Ngo M. Katherine Holloway Ming-Tain Lai Amy S. Espeseth Xiao-Ping Shi Dennis Colussi Beth Pietrak Ming-Chih Crouthamel Katherine Tugusheva Qian Huang Min Xu Adam J. Simon Joseph P. Vacca 《Bioorganic & medicinal chemistry letters》2010,20(6):1885-1889
The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pKa of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Αβ production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5. 相似文献
2.
Luo Y Smith RA Guan R Liu X Klinghofer V Shen J Hutchins C Richardson P Holzman T Rosenberg SH Giranda VL 《Biochemistry》2004,43(5):1254-1263
We have designed peptide inhibitors that potently inhibit Akt both in vitro and inside cells. These peptide inhibitors are selective for Akt versus other closely related kinases. The peptides inhibit the in vitro phosphorylation of a biotinylated Bad peptide by Akt with potency up to 100 nM. We have shown that the binding between Akt1 and these peptide inhibitors requires MgATP. Mutating the two putative Akt phosphorylation sites to Ala (nonsubstrate) in these peptides increases the inhibitory potency while mutating the sites to aspartic acid (phosphorylation mimetic) reduces the potency. When delivered into cells, these peptide inhibitors can inhibit cellular Akt activity and cell growth. Thus, these Akt-specific peptide inhibitors provide prototypes for peptide mimetic drugs as well as very useful tools to dissect cellular functions of Akt. 相似文献
3.
Saraiva L Fresco P Pinto E Gonçalves J 《Journal of enzyme inhibition and medicinal chemistry》2003,18(6):475-483
The aim of the present study was to compare the potency of a series of widely used PKC inhibitors acting either at the regulatory (NPC 15437, tamoxifen and D-sphingosine) or at the catalytic domain (Ro 32-0432, chelerythrine and rottlerin) on individual mammalian PKC isoforms of the classical (alpha and betaI), novel (delta and eta) and atypical (zeta) PKC families, using the yeast phenotypic assay, in order to determine their isoform-selectivity. The PKC inhibitors studied presented differences in their ability to reduce the effect of the appropriate PKC activator (estimated as EC50 ratios) which was interpreted as an index of PKC inhibitory potency. In general, the more marked inhibition was observed on novel PKC isoforms, particularly on PKC-eta. This study indicates promising isoform-selectivity of some PKC inhibitors, namely NPC 15437 for PKC-eta or rottlerin for both novel PKC isoforms. It also suggests that the PKC domain involved in the inhibition does not seem to be relevant for the potency and isoform-selectivity of PKC inhibitors. 相似文献
4.
Brockhoff M Hau JC Fontana P Zimmermann C Pover AD Erdmann D Chène P 《Journal of enzyme inhibition and medicinal chemistry》2012,27(2):194-200
The protein kinase field is a very active research area in the pharmaceutical industry and many activities are ongoing to identify inhibitors of these proteins. The design of new chemical entities with improved pharmacological properties requires a deeper understanding of the factors that modulate inhibitor-kinase interactions. In this report, we studied the effect of two of these factors--the magnesium ion cofactor and the protein substrate--on inhibitors of the type I insulin-like growth factor receptor. Our results show that the concentration of magnesium ion influences the potency of adenosine triphosphate (ATP) competitive inhibitors, suggesting an explanation for the observation that such compounds retain their nanomolar potency in cells despite the presence of millimolar levels of ATP. We also showed that the peptidic substrate affects the potency of these inhibitors in a different manner, suggesting that the influence of this substrate on compound potency should be taken into consideration during drug discovery. 相似文献
5.
《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
6.
Lee McDermott David Koes Shabber Mohammed Prema Iyer Melissa Boby Venkatakrishnan Balasubramanian Mackenzie Geedy William Katt Richard Cerione 《Bioorganic & medicinal chemistry letters》2019,29(19):126632
Allosteric inhibitors of glutaminase (GAC), such as BPTES, CB-839 and UPGL00019, have great promise as inhibitors of cancer cell growth, but potent inhibitors with drug-like qualities have been difficult to achieve. Here, a small library of GAC inhibitors based on the UPGL00019 core is described. This set of derivatives was designed to assess if one or both of the phenylacetyl groups flanking the UPGL00019 core can be replaced by smaller simple aliphatic acyl groups without loss in potency. We found that one of the phenylacetyl moieties can be replaced by a set of small aliphatic moieties without loss in potency. We also found that enzymatic potency co-varies with the VDW volume or the maximum projection area of the groups used as replacements of the phenylacetyl moiety and used literature X-ray data to provide an explanation for this finding. 相似文献
7.
Daniel G. Silva Jean F.R. Ribeiro Daniela De Vita Lorenzo Cianni Caio Haddad Franco Lucio H. Freitas-Junior Carolina Borsoi Moraes Josmar R. Rocha Antonio C.B. Burtoloso Peter W. Kenny Andrei Leitão Carlos A. Montanari 《Bioorganic & medicinal chemistry letters》2017,27(22):5031-5035
The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the α methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude. 相似文献
8.
David R. Anderson Marvin J. Meyers Ravi G. Kurumbail Nicole Caspers Gennadiy I. Poda Scott A. Long Betsy S. Pierce Matthew W. Mahoney Robert J. Mourey 《Bioorganic & medicinal chemistry letters》2009,19(16):4878-4881
Identification of potent benzothiophene inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK2), structure–activity relationship (SAR) studies, selectivity assessments against CDK2, cellular potency and mechanism of action are presented. Crystallographic data provide a rationale for the observed MK2 potency as well as selectivity over CDK2 for this class of inhibitors. 相似文献
9.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):194-200
The protein kinase field is a very active research area in the pharmaceutical industry and many activities are ongoing to identify inhibitors of these proteins. The design of new chemical entities with improved pharmacological properties requires a deeper understanding of the factors that modulate inhibitor–kinase interactions. In this report, we studied the effect of two of these factors—the magnesium ion cofactor and the protein substrate—on inhibitors of the type I insulin-like growth factor receptor. Our results show that the concentration of magnesium ion influences the potency of adenosine triphosphate (ATP) competitive inhibitors, suggesting an explanation for the observation that such compounds retain their nanomolar potency in cells despite the presence of millimolar levels of ATP. We also showed that the peptidic substrate affects the potency of these inhibitors in a different manner, suggesting that the influence of this substrate on compound potency should be taken into consideration during drug discovery. 相似文献
10.
Mahmood- Ul-Hassan Zahid H. Chohan Andrea Scozzafava Claudiu T. Supuran 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):263-267
Schiff's bases were obtained from aromatic/heterocyclic sulfonamides and amino-sulfonamide derivatives, such as sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and 5-amino-1,3,4-thiadiazole-2-sulfonamide. Metal complexes of some of these Schiff's bases, incorporating Zn(II), Co(II), Ni(II) and Cu(II) ions, were also prepared and tested as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more specifically the red blood cell isozymes I and II. The Schiff's bases behaved as medium potency CA I and CA II inhibitors, whereas their metal complexes showed a highly enhanced potency, with several low nanomolar CA II inhibitors detected. 相似文献
11.
Assessment of the potency of 1-substituted cyclopropenes to counteract ethylene-induced processes in plants 总被引:3,自引:0,他引:3
Akiva Apelbaum Edward C. Sisler Xuqiao Feng Raphael Goren 《Plant Growth Regulation》2008,55(2):101-113
A study was undertaken to assess the potency of 1-methylcyclopropene (1-MCP) analogues to block the ethylene receptor and
thereby inhibit ethylene action. Eight structural analogues of 1-MCP with substitution in the 1-position and a side chain
containing 2–10 carbons were synthesized and their potency to inhibit ethylene-induced plant processes was tested on climacteric
fruit like avocado, and tomato, on ethylene-induced growth modification in etiolated pea seedlings and on abscission in citrus
leaf explants. High concentrations of ethylene were used under conditions which hasten ethylene-induced processes. The results
showed differences in the responses of the various tissues tested as related to the concentrations of the inhibitors. Some
required much higher concentration to exert the same effect, while some, when applied at the same concentration, blocked the
receptor for a longer period of time than the others. Fruits responded differently than other plant organs to the same inhibitor,
indicating possible differences in characteristics and availability of the ethylene receptors in the various tissues. The
potency of the inhibitors was greatly affected by their molecular structure and size. The highest potency of a given inhibitor
was obtained when the treatment was applied before the onset of ethylene action. The relationship between ethylene and the
inhibitors was found to be of an apparent non-competitive nature. All the fruits treated with the various inhibitors resumed
normal ripening after recovery from the inhibition which is crucial when considering the putative inhibitors for practical
use. 相似文献
12.
Jeremy P. Mallari Wendyam A. Guiguemde R. Kiplin Guy 《Bioorganic & medicinal chemistry letters》2009,19(13):3546-3549
Malaria is a devastating illness caused by multiple species of the Plasmodium genus. The parasite’s falcipain proteases have been extensively studied as potential drug targets. Here we report the testing of two established cysteine protease inhibitor scaffolds against both chloroquine sensitive and chloroquine resistant parasites. A subset of purine derived nitriles killed the parasite with moderate potency, and these inhibitors do not seem to exert their antiproliferative effects as cysteine protease inhibitors. Compound potency was determined to be similar against both parasite strains, indicating a low probability of cross resistance with chloroquine. These compounds represent a novel antimalarial scaffold, and a potential starting point for the development new inhibitors. 相似文献
13.
Bi Y Stoy P Adam L He B Krupinski J Normandin D Pongrac R Seliger L Watson A Macor JE 《Bioorganic & medicinal chemistry letters》2004,14(6):1577-1580
In a continuing effort to discover novel chemotypes as potent and selective PDE5 inhibitors for the treatment of male erectile dysfunction (ED), we have found that 4-benzylaminoquinoline derivatives are very potent and selective PDE5 inhibitors. Some compounds in this series had PDE5 IC(50)'s as low as 50 pM. While an electron withdrawing group at the C6-position of the quinoline substantially improved PDE5 potency, an ethyl group at the C8-position not only improved the PDE5 potency but also the isozyme selectivity. Substitutents at the C3-position can incorporate a variety of different groups. The synthesis and primary structure-activity relationship of this new series of potent PDE5 inhibitors are described. 相似文献
14.
We describe a novel method to synthesize activated polymers of controlled molecular weight and apply this method to investigate the relationship between the structure and activity of polyvalent inhibitors of anthrax toxin. In particular, we observe an initial sharp increase in potency with increasing ligand density, followed by a plateau where potency is independent of ligand density. Our simple strategy for designing polyvalent inhibitors of controlled molecular weight and ligand density will be broadly applicable for designing inhibitors for a variety of pathogens and toxins, and for elucidating structure-activity relationships in these systems. Our results also demonstrate a role for kinetics in influencing inhibitory potency in polyvalent systems. Finally, our work presents a synthetic route to polyvalent inhibitors that are more structurally defined and effective in vivo. This control over inhibitor composition will be generally useful for the optimization of inhibitor potency and pharmacokinetics, and for the eventual application of these molecules in vivo. 相似文献
15.
Magnin DR Taunk PC Robertson JG Wang A Marcinkeviciene J Kirby MS Hamann LG 《Bioorganic & medicinal chemistry letters》2006,16(6):1731-1734
A series of seco-prolinenitrile-containing dipeptides were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV, a promising new target for treatment of type 2 diabetes. The inhibitors described herein assess the minimum structural requirements at P1 for this enzyme, resulting in the identification of inhibitors with low nM potency. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2014,24(9):2222-2225
Novel triazolopyrimidine acylsulfonamides class of antimycobacterial agents, which are mycobacterial acetohydroxyacid synthase (AHAS) inhibitors were designed by hybridization of known AHAS inhibitors such as sulfonyl urea and triazolopyrimidine sulfonamides. This Letter describes the synthesis and SAR studies of this class of molecules by variation of two parts of the molecule, the phenyl and triazolopyrimidine rings. SAR study describes optimisation of enzyme potency, whole cell potency and evidence of mechanism of action. 相似文献
17.
Keith R. Hornberger Dan M. Berger Andrew P. Crew Hanqing Dong Andrew Kleinberg An-Hu Li Matthew R. Medeiros Mark J. Mulvihill Kam Siu James Tarrant Jing Wang Felix Weng Victoria L. Wilde Mark Albertella Mark Bittner Andrew Cooke Michael J. Gray Paul Maresca Brianna Tokar 《Bioorganic & medicinal chemistry letters》2013,23(16):4517-4522
The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ~10 nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization. 相似文献
18.
Abha Sood Mohammed Abid Samson Hailemichael Michelle Foster Béla Török Marianna Török 《Bioorganic & medicinal chemistry letters》2009,19(24):6931-6934
The effect of enantiomeric trifluoromethyl-indolyl-acetic acid ethyl esters on the fibrillogenesis of Alzheimer’s amyloid β (Aβ) peptide is described. These compounds have been previously identified as effective inhibitors of the Aβ self-assembly in their racemic form. Thioflavin-T Fluorescence Spectroscopy and Atomic Force Microscopy were applied to assess the potency of the chiral target compounds. Both enantiomers showed significant inhibition in the in vitro assays. The potency of the enantiomeric inhibitors appeared to be very similar to each other suggesting the lack of the stereospecific binding interactions between these small molecule inhibitors and the Aβ peptide. 相似文献
19.
Various 3-cyclopropanecarbonyloxy-2-cyclohexen-1-one 1 derivatives have been synthesized and tested as inhibitors of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) from pig liver. The inhibition results indicated that well-positioned dicarbonyl groups as well as the cyclopropyl group of 1 were essential for potent inhibition. Substitution at the 2-position of the ring system has a significant effect on inhibitor potency, while the 5-position can undergo substantial variations and retain inhibitor potency. In the compounds examined, 2-chloro substituted 12 is the best inhibitor of all with IC(50) of 15 nM, the rest of the synthesized analogues were less potent inhibitors than the parent compound. 相似文献
20.
Grunewald GL Seim MR Bhat SR Wilson ME Criscione KR 《Bioorganic & medicinal chemistry》2008,16(1):542-559
A series of substituted 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (THTPs) was synthesized and evaluated for their human phenylethanolamine N-methyltransferase (hPNMT) inhibitory potency and affinity for the alpha(2)-adrenoceptor. The THTP nucleus was suggested as an isosteric replacement for the 1,2,3,4-tetrahydroisoquinoline (THIQ) ring system on the basis that 3-thienylmethylamine (18) was more potent as an inhibitor of hPNMT and more selective toward the alpha(2)-adrenoceptor than benzylamine (15). Although the isosterism was confirmed, with similar influence of functional groups and chirality in both systems on hPNMT inhibitory potency and selectivity, the THTP compounds proved, in general, to be less potent as inhibitors of hPNMT than their THIQ counterparts, with the drop in potency being primarily attributed to the electronic properties of the thiophene ring. A hypothesis for the reduced hPNMT inhibitory potency of these compounds has been formed on the basis of molecular modeling and docking studies using the X-ray crystal structures of hPNMT co-crystallized with THIQ-type inhibitors and S-adenosyl-L-homocysteine as a template. 相似文献