共查询到20条相似文献,搜索用时 15 毫秒
1.
de Jong JC Sørensen LG Tornqvist H Jacobsen P 《Bioorganic & medicinal chemistry letters》2004,14(7):1741-1744
The central role of adipose tissue hormone-sensitive lipase in regulating fatty acid metabolism makes it a potential pharmacological target for the prevention of peripheral insulin resistance in obese, prediabetic and diabetic individuals. The synthesis of a new series of carbazates is presented. Modification of the phenolic 4-position in a series of 1,2,3,4-tetrahydroisoquinoline and morpholine derived carbazates, yielded inhibitors of the catalytic activity of this enzyme with nanomolar potency. 相似文献
2.
Das J Furch JA Liu C Moquin RV Lin J Spergel SH McIntyre KW Shuster DJ O'Day KD Penhallow B Hung CY Doweyko AM Kamath A Zhang H Marathe P Kanner SB Lin TA Dodd JH Barrish JC Wityak J 《Bioorganic & medicinal chemistry letters》2006,16(14):3706-3712
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity, and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 3 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo and was previously reported to reduce lung inflammation in a mouse model of ovalbumin induced allergy/asthma. 相似文献
3.
Dengyou Zhang Jing Ai Zhongjie Liang Wei Zhu Xia Peng Xianjie Chen YinChun Ji Hualiang Jiang Cheng Luo Meiyu Geng Hong Liu 《Bioorganic & medicinal chemistry letters》2013,23(8):2408-2413
A series of novel 5-(benzyloxy)pyridin-2(1H)-ones were designed, synthesized and biologically evaluated for c-Met inhibition. Various amides and benzoimidazoles at C-3 position were investigated. A potent compound 12b with a c-Met IC50 of 12 nM was identified. This compound exhibited potent inhibition of EBC-1 cell associated with c-Met constitutive activation and showed high selectivity for c-Met than other tested 11 kinases. The binding model 12b with c-Met was disclosed by docking analysis. 相似文献
4.
Li G Hasvold LA Tao ZF Wang GT Gwaltney SL Patel J Kovar P Credo RB Chen Z Zhang H Park C Sham HL Sowin T Rosenberg SH Lin NH 《Bioorganic & medicinal chemistry letters》2006,16(8):2293-2298
Based on the X-ray crystallography of our lead compound 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint kinase 1 (Chk1) enzyme, we modified R4, and to a lesser extent, R2, and R5 of the phenyl ring, and made a variety of N-aryl-N'-pyrazinylurea Chk1 inhibitors. Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound 8i provided the best overall results in the cellular assays as it abrogated doxorubicin-induced cell cycle arrest (IC50=1.7 microM) and enhanced doxorubicin cytotoxicity (IC50=0.44 microM) while displaying no single agent activity. 相似文献
5.
Deak HL Newcomb JR Nunes JJ Boucher C Cheng AC DiMauro EF Epstein LF Gallant P Hodous BL Huang X Lee JH Patel VF Schneider S Turci SM Zhu X 《Bioorganic & medicinal chemistry letters》2008,18(3):1172-1176
N-3-(Phenylcarbamoyl)arylpyrimidine-5-carboxamides are a novel class of selective Lck inhibitors. This series of compounds derives its selectivity from a hydrogen bond with the gatekeeper Thr316 of the enzyme. X-ray co-crystal structural data, structure-activity relationships, and the synthesis of these inhibitors are reported herein. 相似文献
6.
Shafer CM Lindvall M Bellamacina C Gesner TG Yabannavar A Jia W Lin S Walter A 《Bioorganic & medicinal chemistry letters》2008,18(16):4482-4485
A series of 4-(4-hydroxyphenyl)-6-phenylpyrimidin-2(1H)-ones were identified by HTS as inhibitors of CDC7. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus on removing potential metabolic liabilities and improving cellular potency. 相似文献
7.
Andrew S. Rosenthal Thomas S. Dexheimer Opher Gileadi Giang H. Nguyen Wai Kit Chu Ian D. Hickson Ajit Jadhav Anton Simeonov David J. Maloney 《Bioorganic & medicinal chemistry letters》2013,23(20):5660-5666
Human cells utilize a variety of complex DNA repair mechanisms in order to combat constant mutagenic and cytotoxic threats from both exogenous and endogenous sources. The RecQ family of DNA helicases, which includes Bloom helicase (BLM), plays an important function in DNA repair by unwinding complementary strands of duplex DNA as well as atypical DNA structures such as Holliday junctions. Mutations of the BLM gene can result in Bloom syndrome, an autosomal recessive disorder associated with cancer predisposition. BLM-deficient cells exhibit increased sensitivity to DNA damaging agents indicating that a selective BLM inhibitor could be useful in potentiating the anticancer activity of these agents. In this work, we describe the medicinal chemistry optimization of the hit molecule following a quantitative high-throughput screen of >355,000 compounds. These efforts lead to the identification of ML216 and related analogs, which possess potent BLM inhibition and exhibit selectivity over related helicases. Moreover, these compounds demonstrated cellular activity by inducing sister chromatid exchanges, a hallmark of Bloom syndrome. 相似文献
8.
Bosse TD Larson DP Wagner R Hutchinson DK Rockway TW Kati WM Liu Y Masse S Middleton T Mo H Montgomery D Jiang W Koev G Kempf DJ Molla A 《Bioorganic & medicinal chemistry letters》2008,18(2):568-570
A series of gem-dialkyl naphthalenone derivatives with varied alkyl substitutions were synthesized and evaluated according to their structure-activity relationship. This investigation led to the discovery of potent inhibitors of the hepatitis C virus at low nanomolar concentrations in both enzymatic and cell-based HCV genotype 1a assays. 相似文献
9.
Jia ZJ Wu Y Huang W Zhang P Song Y Woolfrey J Sinha U Arfsten AE Edwards ST Hutchaleelaha A Hollennbach SJ Lambing JL Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2004,14(5):1229-1234
Using N,N-dialkylated benzamidines as the novel P4 motifs, we have designed and synthesized a class of 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent and selective fXa inhibitors with significantly improved hydrophilicity and in vitro anticoagulant activity. These benzamidine-P4 fXa inhibitors have displayed excellent oral bioavailability and long half-life. 相似文献
10.
Ontoria JM Bufi LL Torrisi C Bresciani A Giomini C Rowley M Serafini S Bin H Hao W Steinkühler C Jones P 《Bioorganic & medicinal chemistry letters》2011,21(18):5274-5282
The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway. 相似文献
11.
Laszlo Revesz Achim Schlapbach Reiner Aichholz Janet Dawson Roland Feifel Stuart Hawtin Amanda Littlewood-Evans Guido Koch Markus Kroemer Henrik Möbitz Clemens Scheufler Juraj Velcicky Christine Huppertz 《Bioorganic & medicinal chemistry letters》2010,20(15):4719-4723
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D–E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC50 <3 nM and inhibit the release of TNFα (IC50<0.3 μM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC50 = 0.05–0.23 μM), less potent in cells (IC50 <1.1 μM), but show good oral absorption. Compound 13E (100 mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score. 相似文献
12.
Laszlo Revesz Achim Schlapbach Reiner Aichholz Roland Feifel Stuart Hawtin Richard Heng Peter Hiestand Wolfgang Jahnke Guido Koch Markus Kroemer Henrik Möbitz Clemens Scheufler Juraj Velcicky Christine Huppertz 《Bioorganic & medicinal chemistry letters》2010,20(15):4715-4718
Pyrrolo[2,3-f]isoquinoline based amino acids, tetracyclic lactams and cyclic ketone analogues are described as novel MK2 inhibitors with IC50 as low as 5 nM and good selectivity profiles against a number of related kinases including ERK, p38α and JNKs. TNFα release was suppressed from human peripheral blood mononuclear cells (hPBMCs), and a representative compound inhibited LPS induced TNFα release in mice illustrating the potential of this series to provide orally active MK2 inhibitors. 相似文献
13.
Das J Liu C Moquin RV Lin J Furch JA Spergel SH Doweyko AM McIntyre KW Shuster DJ O'Day KD Penhallow B Hung CY Kanner SB Lin TA Dodd JH Barrish JC Wityak J 《Bioorganic & medicinal chemistry letters》2006,16(9):2411-2415
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 2 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo. 相似文献
14.
Amir Assadieskandar Mohsen Amini Marjan Salehi Hamid Sadeghian Maliheh Alimardani Amirhossein Sakhteman Hamid Nadri Abbas Shafiee 《Bioorganic & medicinal chemistry》2012,20(24):7160-7166
A series of 4,5-diaryl-1H-imidazole-2(3H)-thione was synthesized and their inhibitory potency against soybean 15-lipoxygenase and free radical scavenging activities were determined. Compound 11 showed the best IC50 for 15-LOX inhibition (IC50 = 4.7 μM) and free radical scavenging activity (IC50 = 14 μM). Methylation of SH at C2 position of imidazole has dramatically decreased the 15-LOX inhibition and radical scavenging activity as it can be observed in the inactive compound 14 (IC50 >250 μM). Structure activity similarity (SAS) showed that the most important chemical modification in this series was methylation of SH group and Docking studies revealed a proper orientation for SH group towards Fe core of the 15-LOX active site. Therefore it was concluded that iron chelating could be a possible mechanism for enzyme inhibition in this series of compounds. 相似文献
15.
Bamborough P Christopher JA Cutler GJ Dickson MC Mellor GW Morey JV Patel CB Shewchuk LM 《Bioorganic & medicinal chemistry letters》2006,16(24):6236-6240
The identification and hit-to-lead exploration of a novel, potent and selective series of substituted benzimidazole–thiophene carbonitrile inhibitors of IKK-ε kinase is described. Compound 12e was identified with an IKK-ε enzyme potency of pIC50 7.4, and has a highly encouraging wider selectivity profile, including selectivity within the IKK kinase family. 相似文献
16.
Zhong W Liu H Kaller MR Henley C Magal E Nguyen T Osslund TD Powers D Rzasa RM Wang HL Wang W Xiong X Zhang J Norman MH 《Bioorganic & medicinal chemistry letters》2007,17(19):5384-5389
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine protein kinase and its deregulation is implicated in a number of neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Using active site homology modeling between CDK5 and CDK2, we explored several different chemical series of potent CDK5 inhibitors. In this report, we describe the design, synthesis, and CDK5 inhibitory activities of quinolin-2(1H)-one derivatives. 相似文献
17.
Dumas J Hatoum-Mokdad H Sibley R Riedl B Scott WJ Monahan MK Lowinger TB Brennan C Natero R Turner T Johnson JS Schoenleber R Bhargava A Wilhelm SM Housley TJ Ranges GE Shrikhande A 《Bioorganic & medicinal chemistry letters》2000,10(18):2051-2054
Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM). 相似文献
18.
Li J Lynch MP Demello KL Sakya SM Cheng H Rafka RJ Bronk BS Jaynes BH Kilroy C Mann DW Haven ML Kolosko NL Petras C Seibel SB Lund LA 《Bioorganic & medicinal chemistry》2005,13(5):1805-1809
The synthesis of a novel canine COX-2 selective inhibitor, 2-(3-difluoromethyl-5-phenylpyrazol-1-yl)-5-methanesulfonylpyridine, and its in vitro and in vivo profile are described. Pyrazole 8 demonstrated excellent potency and selectivity for canine COX-2 in both in vitro and ex vivo whole blood assays. This novel COX-2 inhibitor also showed a good pharmacokinetic profile (pk) following oral (po), intravenous (iv), and subcutaneous (sc) dosing and demonstrated excellent in vivo efficacy in a canine synovitis model. 相似文献
19.
Claudia Vergelli Igor A. Schepetkin Antonella Iacovone Maria Paola Giovannoni Gabriella Guerrini 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):821-831
Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC50 value =20?nM) and chemical stability in aqueous buffer (t1/2=8.9?h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds 2o and 2s contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups. 相似文献
20.
Inguimbert N Poras H Teffo F Beslot F Selkti M Tomas A Scalbert E Bennejean C Renard P Fournié-Zaluski MC Roques BP 《Bioorganic & medicinal chemistry letters》2002,12(15):2001-2005
We have previously reported the design of a lead compound 1a for the joint inhibition of neprilysin (NEP, EC 3.4.24.11), angiotensin converting enzyme (ACE, EC 3.4.15.1) and endothelin converting enzyme (ECE-1, EC 3.4.24.71), three metallopeptidases which are implicated in the regulation of fluid homeostasis and vascular tone. We report here the synthesis and biological activities of analogues derived from this lead with inhibitory potencies in the nanomolar range for the three enzymes. Compounds 8b and 15c are the most potent triple inhibitors described to date. 相似文献