共查询到20条相似文献,搜索用时 31 毫秒
1.
Zhang X Pais GC Svarovskaia ES Marchand C Johnson AA Karki RG Nicklaus MC Pathak VK Pommier Y Burke TR 《Bioorganic & medicinal chemistry letters》2003,13(6):1215-1219
Aryl beta-diketo acids (ADK) comprise a general class of potent HIV-1 integrase (IN) inhibitors, which can exhibit selective inhibition of strand transfer reactions in extracellular recombinant IN assays and provide potent antiviral effects in HIV-infected cells. Recent studies have shown that polycyclic aryl or aryl rings bearing aryl-containing substituents are components of potent members of this class. Reported herein is the first use of azido functionality as an aryl replacement in beta-diketo acid IN inhibitors. The ability of azido-containing inhibitors to exhibit potent inhibition of IN and antiviral protection in HIV-infected cells, renders the azide group of potential value in the further development of ADK-based IN inhibitors. 相似文献
2.
Hansen JD Grina J Newhouse B Welch M Topalov G Littman N Callejo M Gloor S Martinson M Laird E Brandhuber BJ Vigers G Morales T Woessner R Randolph N Lyssikatos J Olivero A 《Bioorganic & medicinal chemistry letters》2008,18(16):4692-4695
Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies. 相似文献
3.
Thyroglobulin type-1 repeats are primarily found in thyroglobulin and several other functionally unrelated proteins. Because a few of them exhibit inhibitory activity against cysteine proteases they were named thyropins (thyroglobulin type-1 domain protease inhibitors). In contrast to cystatins, the best-characterized group of papain-like protease inhibitors, they exhibit greater selectivity in their interactions with target proteases. Interestingly, a few members inhibit aspartic protease cathepsin D and metalloproteases. In contrast to the inhibitory fragment of the major histocompatibility complex class II-associated p41 form of invariant chain, whose structural integrity appears mandatory for its inhibitory properties, short polypeptides derived from insulin-like growth factor-binding proteins exhibit the same activity as the structure of the whole fragment. Taken together, the results indicate that the thyroglobulin type-1 repeat is a structural motif occasionally employed as an inhibitor of proteases. 相似文献
4.
Dumas J Sibley R Riedl B Monahan MK Lee W Lowinger TB Redman AM Johnson JS Kingery-Wood J Scott WJ Smith RA Bobko M Schoenleber R Ranges GE Housley TJ Bhargava A Wilhelm SM Shrikhande A 《Bioorganic & medicinal chemistry letters》2000,10(18):2047-2050
The MAP kinase p38 has been implicated in cytokine signaling, and its inhibitors are potentially useful for the treatment of arthritis and osteoporosis. Novel small-molecule inhibitors of p38 kinase were derived from a combinatorial chemistry effort and exhibit activity in the nanomolar range. Very steep structure-activity relationships are observed within this class. 相似文献
5.
Zhijian Zhao William H. Leister Julie A. O’Brien Wei Lemaire David L. Williams Marlene A. Jacobson Cyrille Sur Gene G. Kinney Doug J. Pettibone Philip R. Tiller Sheri Smith George D. Hartman Craig W. Lindsley Scott E. Wolkenberg 《Bioorganic & medicinal chemistry letters》2009,19(5):1488-1491
Employing an iterative analogue library approach, novel potent and selective glycine transporter 1 (GlyT1) inhibitors containing a 4-pyridin-2-ylpiperidine sulfonamide have been discovered. These inhibitors are devoid of time-dependent CYP inhibition activity and exhibit improved aqueous solubility versus the corresponding 4-phenylpiperidine analogues. 相似文献
6.
Compounds that inhibit gamma-aminobutyric acid aminotransferase exhibit anticonvulsant activity; vigabatrin is a known irreversible inhibitor of this enzyme and anticonvulsant drug. Conformationally-restricted, five-membered- and six-membered-ring vigabatrin analogs were synthesized and tested as inhibitors of gamma-aminobutyric acid aminotransferase. Two monofluorinated compounds, 4 and 5, are time-dependent inhibitors of the enzyme, and their potencies are comparable to that of vigabatrin. Compounds 6 and 7 are weak reversible inhibitors. 相似文献
7.
M R Michaelides J F Dellaria J Gong J H Holms J J Bouska J Stacey C K Wada H R Heyman M L Curtin Y Guo C L Goodfellow I B Elmore D H Albert T J Magoc P A Marcotte D W Morgan S K Davidsen 《Bioorganic & medicinal chemistry letters》2001,11(12):1553-1556
A novel series of biaryl ether reverse hydroxamate MMP inhibitors has been developed. These compounds are potent MMP-2 inhibitors with limited activity against MMP-1. Select members of this series exhibit excellent pharmacokinetic properties with long elimination half-lives (7 h) and high oral bioavailability (100%). 相似文献
8.
Sonja Nordhoff Stephan Bulat Silvia Cerezo-Glvez Oliver Hill Barbara Hoffmann-Enger Meritxell Lpez-Canet Claudia Rosenbaum Christian Rummey Meinolf Thiemann Victor G. Matassa Paul J. Edwards Achim Feurer 《Bioorganic & medicinal chemistry letters》2009,19(22):6340-6345
For a series of β-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes. 相似文献
9.
Yonetoku Y Kubota H Okamoto Y Ishikawa J Takeuchi M Ohta M Tsukamoto S 《Bioorganic & medicinal chemistry》2006,14(15):5370-5383
To identify potent and selective calcium-release-activated calcium (CRAC) channel inhibitors, we examined the structure-activity relationships of the pyrazole and thiophene moieties in compound 4. Compound 25b was found to exhibit highly potent and selective inhibitory activity for CRAC channels and further modifications of the pyrazole and benzoyl moieties of compound 25b produced compound 29. These compounds were potent inhibitors of IL-2 production in vitro and also acted as inhibitors in pharmacological models of diseases resulting from T-lymphocyte activation, after oral administration. 相似文献
10.
采后果蔬对乙烯受体抑制剂的响应及贮运保鲜技术的研究 总被引:4,自引:0,他引:4
近几年来 ,随着重氮环戊二烯和环丙烯类等乙烯受体抑制剂的发现 ,为控制乙烯敏感型的果蔬采后成熟、衰老提供新的技术手段。从乙烯受体抑制剂的特性、作用特点以及可能作用机理等方面概述了采后果蔬对乙烯受体抑制剂的响应和应用乙烯受体抑制剂延长采后果蔬贮运保鲜的技术。 相似文献
11.
Ren L Laird ER Buckmelter AJ Dinkel V Gloor SL Grina J Newhouse B Rasor K Hastings G Gradl SN Rudolph J 《Bioorganic & medicinal chemistry letters》2012,22(2):1165-1168
Herein we describe a novel series of ATP competitive B-Raf inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with improved physicochemical and pharmacokinetic properties. 相似文献
12.
Menear KA Adcock C Alonso FC Blackburn K Copsey L Drzewiecki J Fundo A Le Gall A Gomez S Javaid H Lence CF Martin NM Mydlowski C Smith GC 《Bioorganic & medicinal chemistry letters》2008,18(14):3942-3945
We have previously described poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors based on a substituted benzyl-phthalazinone scaffold. As an alternative chemical template, a novel series of alkoxybenzamides were developed with restricted conformation through intramolecular hydrogen bond formation; the compounds exhibit low nM enzyme and cellular activity as PARP-1 inhibitors. 相似文献
13.
Topoisomerases are known to aid DNA replication by breaking and resealing supercoiled DNA. Consequently, cells exposed to topoisomerase inhibitors before or during the S (DNA synthetic) phase of the cell cycle undergo abnormal DNA replication and become irreversibly blocked in the G2 (pre-mitosis) phase. We report that following a 4-h exposure to topoisomerase II inhibitors, murine erythroleukemic cells (MELC) do not form mitotic figures but exhibit a time-dependent progression into G2 (4N DNA) and greater than G2 (up to 8N DNA) stages of the cell cycle. Following exposure to the topoisomerase I inhibitor camptothecin, recovering MELC also exhibit greater than G2 polyploidy, but to a considerably lesser degree: mitotic figures are present and a subpopulation of cells resumes cycling. However, both topo I and topo II inhibitors induce maximal percentages of greater than G2 cells when synchronized MELC are in the G2/M phase at the time of exposure. This suggests that, in addition to their S-phase action, topoisomerase inhibitors can interfere with chromosome condensation during G2 and, in so doing, induce polyploidy. 相似文献
14.
Kareem N. Mohni Petria S. Thompson Jessica W. Luzwick Gloria G. Glick Christopher S. Pendleton Brian D. Lehmann Jennifer A. Pietenpol David Cortez 《PloS one》2015,10(5)
The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic. 相似文献
15.
Discovery and structure-activity relationships of novel sulfonamides as potent PTP1B inhibitors 总被引:2,自引:0,他引:2
Holmes CP Li X Pan Y Xu C Bhandari A Moody CM Miguel JA Ferla SW De Francisco MN Frederick BT Zhou S Macher N Jang L Irvine JD Grove JR 《Bioorganic & medicinal chemistry letters》2005,15(19):4336-4341
A series of novel sulfonamides containing a single difluoromethylene-phosphonate group were discovered to be potent inhibitors of protein tyrosine phosphatase 1B. Structure-activity relationships around the scaffold were investigated, leading to the identification of compounds with IC50 or Ki values in the low nanomolar range. These sulfonamide-based inhibitors exhibit 100 and 30 times higher inhibitory activity than the corresponding tertiary amines and carboxamides, respectively. 相似文献
16.
Ye P Kuhn C Juan M Sharma R Connolly B Alton G Liu H Stanton R Kablaoui NM 《Bioorganic & medicinal chemistry letters》2011,21(2):849-852
S6K1 (p70 S6 kinase-1) is thought to play a critical role in the development of obesity and insulin resistance, thus making it an attractive target in developing medicines for the treatment of these disorders. We describe a novel thiophene urea class of S6K inhibitors. The lead matter for the development of these inhibitors came from mining the literature for reports of weak off-target S6K activity. These optimized inhibitors exhibit good potency and excellent selectivity for S6K over a panel of 43 kinases. 相似文献
17.
Ren L Ahrendt KA Grina J Laird ER Buckmelter AJ Hansen JD Newhouse B Moreno D Wenglowsky S Dinkel V Gloor SL Hastings G Rana S Rasor K Risom T Sturgis HL Voegtli WC Mathieu S 《Bioorganic & medicinal chemistry letters》2012,22(10):3387-3391
Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. 相似文献
18.
Irie O Kosaka T Kishida M Sakaki J Masuya K Konishi K Yokokawa F Ehara T Iwasaki A Iwaki Y Hitomi Y Toyao A Gunji H Teno N Iwasaki G Hirao H Kanazawa T Tanabe K Hiestand PC Malcangio M Fox AJ Bevan SJ Yaqoob M Culshaw AJ Hart TW Hallett A 《Bioorganic & medicinal chemistry letters》2008,18(19):5280-5284
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain. 相似文献
19.
Beaulieu C Isabel E Fortier A Massé F Mellon C Méthot N Ndao M Nicoll-Griffith D Lee D Park H Black WC 《Bioorganic & medicinal chemistry letters》2010,20(24):7444-7449
Identification of potent and reversible cruzipain inhibitors for the treatment of Chagas disease is described. The identified inhibitors bearing an amino nitrile warhead in P1 exhibit low nanomolar in vitro potency against cruzipain. Further SAR in P2 portion led to the identification of compounds, such as 26, that have a unique selectivity profile against other cysteine proteases and offering new opportunities for safer treatment of Chagas disease. 相似文献
20.
Novel cell-penetrating alpha-keto-amide calpain inhibitors as potential treatment for muscular dystrophy 总被引:1,自引:0,他引:1
Lescop C Herzner H Siendt H Bolliger R Henneböhle M Weyermann P Briguet A Courdier-Fruh I Erb M Foster M Meier T Magyar JP von Sprecher A 《Bioorganic & medicinal chemistry letters》2005,15(23):5176-5181
Dipeptide-derived alpha-keto-amide compounds with potent calpain inhibitory activity have been identified. These reversible covalent inhibitors have IC(50) values down to 25nM and exhibit greatly improved activity in muscle cells compared to the reference compound MDL28170. Several novel calpain inhibitors have shown positive effects on histological parameters in an animal model of Duchenne muscular dystrophy demonstrating their potential as a treatment option for this fatal disease. 相似文献