共查询到20条相似文献,搜索用时 15 毫秒
1.
Yeh VS Kurukulasuriya R Fung S Monzon K Chiou W Wang J Stolarik D Imade H Shapiro R Knourek-Segel V Bush E Wilcox D Nguyen PT Brune M Jacobson P Link JT 《Bioorganic & medicinal chemistry letters》2006,16(21):5555-5560
A series of metabolically stable butyrolactam 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles. 相似文献
2.
11beta-Hydroxysteroid dehydrogenase (11beta-HSD) enzymes catalyze the conversion of biologically inactive 11-ketosteroids into their active 11beta-hydroxy derivatives and vice versa. 11beta-HSD1 has been studied as a potential treatment for metabolic disease such as diabetes and obesity. To find correlation between 11beta-HSD1 and inhibitors, three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on 70 inhibitors, based on molecular docking conformations obtained by using FlexX-Pharm. The studies include comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Based on the docking results, highly predictive 3D-QSAR models were developed with q(2) values of 0.543 and 0.519 for CoMFA and CoMSIA, respectively. A comparison of the 3D-QSAR field contributions with the structural features of the binding site showed good correlation between the two analyses. Therefore, these results should be useful to the prediction of the activities of new 11beta-HSD1 inhibitors. 相似文献
3.
Santhosh F. Neelamkavil Craig D. Boyle Samuel Chackalamannil William J. Greenlee Lili Zhang Giuseppe Terracina 《Bioorganic & medicinal chemistry letters》2009,19(16):4563-4565
Discovery of a series of azepine sulfonamides as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is described. SAR studies at the 4-position of the azepane ring have resulted in the discovery of a very potent compound 30 which has an 11β-HSD1 IC50 of 3.0 nM. 相似文献
4.
Webster SP Ward P Binnie M Craigie E McConnell KM Sooy K Vinter A Seckl JR Walker BR 《Bioorganic & medicinal chemistry letters》2007,17(10):2838-2843
A series of adamantyl amide 11beta-HSD1 inhibitors has been discovered and chemically modified. Selected compounds are selective for 11beta-HSD1 over 11beta-HSD2 and possess excellent cellular potency in human and murine 11beta-HSD1 assays. Good pharmacodynamic characteristics are observed in ex vivo assays. 相似文献
5.
Yeh VS Patel JR Yong H Kurukulasuriya R Fung S Monzon K Chiou W Wang J Stolarik D Imade H Beno D Brune M Jacobson P Sham H Link JT 《Bioorganic & medicinal chemistry letters》2006,16(20):5414-5419
A series of metabolically stable adamantane amide 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity and good pharmacokinetic and pharmacodynamic profiles. 相似文献
6.
Sun D Wang Z Di Y Jaen JC Labelle M Ma J Miao S Sudom A Tang L Tomooka CS Tu H Ursu S Walker N Yan X Ye Q Powers JP 《Bioorganic & medicinal chemistry letters》2008,18(12):3513-3516
High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11beta-HSD1 IC(50)=3nM). 相似文献
7.
Yeh VS Kurukulasuriya R Madar D Patel JR Fung S Monzon K Chiou W Wang J Jacobson P Sham HL Link JT 《Bioorganic & medicinal chemistry letters》2006,16(20):5408-5413
A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replacements have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11beta-HSD1 potency and 11beta-HSD2 selectivity. 相似文献
8.
Xiang Y Hirth B Asmussen G Biemann HP Bishop KA Good A Fitzgerald M Gladysheva T Jain A Jancsics K Liu J Metz M Papoulis A Skerlj R Stepp JD Wei RR 《Bioorganic & medicinal chemistry letters》2011,21(10):3050-3056
Novel benzofuran-2-carboxylic acids, exemplified by 29, 38 and 39, have been discovered as potent Pim-1 inhibitors using fragment based screening followed by X-ray structure guided medicinal chemistry optimization. The compounds demonstrate potent inhibition against Pim-1 and Pim-2 in enzyme assays. Compound 29 has been tested in the Ambit 442 kinase panel and demonstrates good selectivity for the Pim kinase family. X-ray structures of the inhibitor/Pim-1 binding complex reveal important salt-bridge and hydrogen bond interactions mediated by the compound’s carboxylic acid and amino groups. 相似文献
9.
Quantitative real-time PCR for the measurement of 11beta-HSD1 and 11beta-HSD2 mRNA levels in tissues of healthy dogs. 总被引:1,自引:0,他引:1
N S Sieber-Ruckstuhl M L Meli F S Boretti E G?nczi H Lutz C E Reusch 《Hormones et métabolisme》2007,39(8):548-554
The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) exists in two isoforms, 11beta-HSD1 and 11beta-HSD2. 11beta-HSD1 generates active cortisol from cortisone and appears to be involved in insulin resistant states. 11beta-HSD2 protects the mineralocorticoid receptor from inappropriate activation by glucocorticoids and is important to prevent sodium retention and hypertension. The purposes of the present study were to develop two real-time PCR assays to assess 11beta-HSD1 and 11beta-HSD2 mRNA expression and to evaluate the tissue distribution of the two isoforms in dogs. Thirteen different tissues of 10 healthy dogs were evaluated. Both real-time PCR assays were highly specific, sensitive and reproducible. Highest 11beta-HSD1 mRNA expression was seen in liver, lung, and renal medulla; highest 11beta-HSD2 mRNA expression in renal cortex, adrenal gland, and renal medulla. Higher 11beta-HSD1 than 11beta-HSD2 mRNA levels were found in all tissues except adrenal gland, colon, and rectum. Our results demonstrate that the basic tissue distribution of 11beta-HSD1 and 11beta-HSD2 in dogs corresponds to that in humans and rodents. In a next step 11beta-HSD1 and 11beta-HSD2 expression should be assessed in diseases like obesity, hypercortisolism, and hypertension to improve our knowledge about 11beta-HSD activity, to evaluate the dog as a model for humans and to potentially find new therapeutic options. 相似文献
10.
Richards S Sorensen B Jae HS Winn M Chen Y Wang J Fung S Monzon K Frevert EU Jacobson P Sham H Link JT 《Bioorganic & medicinal chemistry letters》2006,16(24):6241-6245
High throughput screening efforts have identified a novel class of dichloroaniline amide 11β-HSD1 inhibitors. SAR studies initiated from dichloroaniline 4 focused on retaining the potency and selectivity profile of the lead. 相似文献
11.
Wu JP Wang J Abeywardane A Andersen D Emmanuel M Gautschi E Goldberg DR Kashem MA Lukas S Mao W Martin L Morwick T Moss N Pargellis C Patel UR Patnaude L Peet GW Skow D Snow RJ Ward Y Werneburg B White A 《Bioorganic & medicinal chemistry letters》2007,17(16):4664-4669
The discovery of a series of potent, carboline-based MK2 inhibitors is described. These compounds inhibit MK2 with IC50s as low as 10 nM, as measured in a DELFIA assay. An X-ray crystal structure reveals that they bind in a region near the p-loop and the hinge region of MK2a. 相似文献
12.
The discovery of potent cRaf1 kinase inhibitors 总被引:8,自引:0,他引:8
Lackey K Cory M Davis R Frye SV Harris PA Hunter RN Jung DK McDonald OB McNutt RW Peel MR Rutkowske RD Veal JM Wood ER 《Bioorganic & medicinal chemistry letters》2000,10(3):223-226
A series of benzylidene-1H-indol-2-one (oxindole) derivatives was synthesized and evaluated as cRaf-1 kinase inhibitors. The key features of the molecules were the donor/acceptor motif common to kinase inhibitors and a critical acidic phenol flanked by two substitutions. Diverse 5-position substitutions provided compounds with low nanomolar kinase enzyme inhibition and inhibited the intracellular MAPK pathway. 相似文献
13.
14.
Nuotio-Antar AM Hasty AH Kovacs WJ 《The Journal of steroid biochemistry and molecular biology》2006,99(2-3):93-99
11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1), an NADPH-dependent reductase, functions in intact cells to convert inactive 11-keto metabolites of glucocorticoids into biologically active glucocorticoids. The enzyme is thus capable of amplifying glucocorticoid action in tissues in which it is expressed. In the experiments presented here, we show that 11beta-HSD1 is expressed in the murine thymus and that expression increases from late fetal development to maximal levels in the adult thymus. Quantitative real time-PCR, immunoblots, and assays of enzymatic activity reveal adult thymic expression of 11beta-HSD1 mRNA and protein at levels approximately 6-7% of those observed in liver. Immunofluorescence experiments show that the enzyme is expressed in the medullary thymocytes and thymocytes present at the corticomedullary junction. These experiments extend our recognition of 11beta-HSD1 expression in cells of the immune system and lend support to the notion that glucocorticoid signaling and amplification of those signals by regeneration of active glucocorticoids from inactive 11-keto metabolites might impact intrathymic T cell development and the establishment of the immune repertoire. 相似文献
15.
FB Fahlbusch M Ruebner G Volkert R Offergeld A Hartner C Menendez-Castro R Strick M Rauh W Rascher J Doetsch 《Reproductive biology and endocrinology : RB&E》2012,10(1):80
ABSTRACT: BACKGROUND: The placental syncytiotrophoblast is the major source of maternal plasma corticotropin-releasing hormone (CRH) in the second half of pregnancy. Placental CRH exerts multiple functions in the maternal organism: It induces the adrenal secretion of cortisol via the stimulation of adrenocorticotropic hormone, regulates the timing of birth via its actions in the myometrium and inhibits the invasion of extravillous trophoblast cells in vitro. However, the auto- and paracrine actions of CRH on the syncytiotrophoblast itself are unknown. Intrauterine growth restriction (IUGR) is accompanied by an increase in placental CRH, which could be of pathophysiological relevance for the dysregulation in syncytialisation seen in IUGR placentas. METHODS: We aimed to determine the effect of CRH on isolated primary trophoblastic cells in vitro. After CRH stimulation the trophoblast syncytialisation rate was monitored via syncytin-1 gene expression and beta-hCG (beta-human chorionic gonadotropine) ELISA in culture supernatant. The expression of the IUGR marker genes leptin and 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) was measured continuously over a period of 72 h. We hypothesized that CRH might attenuate syncytialisation, induce leptin, and reduce 11beta-HSD2 expression in primary villous trophoblasts, which are known features of IUGR. RESULTS: CRH did not influence the differentiation of isolated trophoblasts into functional syncytium as determined by beta-hCG secretion, albeit inducing syncytin-1 expression. Following syncytialisation, CRH treatment significantly increased leptin and 11beta-HSD2 expression, as well as leptin secretion into culture supernatant after 48 h. CONCLUSION: The relevance of CRH for placental physiology is underlined by the present in vitro study. The induction of leptin and 11beta-HSD2 in the syncytiotrophoblast by CRH might promote fetal nutrient supply and placental corticosteroid metabolism in the phase before labour induction. 相似文献
16.
Flyrén K Bergquist LO Castro VM Fotsch C Johansson L St Jean DJ Sutin L Williams M 《Bioorganic & medicinal chemistry letters》2007,17(12):3421-3425
A series of piperidine amide inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) were identified via modifications of the HTS hit compound 1. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. 相似文献
17.
Stephen Antonysamy Gavin Hirst Frances Park Paul Sprengeler Frank Stappenbeck Ruo Steensma Mark Wilson Melissa Wong 《Bioorganic & medicinal chemistry letters》2009,19(1):279-282
Fragment-based hit identification coupled with crystallographically enabled structure-based drug design was used to design potent inhibitors of JAK-2. After two iterations from fragment 1, we were able to increase potency by greater than 500-fold to provide sulfonamide 13, a 78-nM JAK-2 inhibitor. 相似文献
18.
Gu X Dragovic J Koo GC Koprak SL LeGrand C Mundt SS Shah K Springer MS Tan EY Thieringer R Hermanowski-Vosatka A Zokian HJ Balkovec JM Waddell ST 《Bioorganic & medicinal chemistry letters》2005,15(23):5266-5269
Replacement of the pentyl chain on our original bicyclo[2.2.2]octyltriazole leads 1 and 2 has led to the discovery that heteroaryl substituted bicyclo[2.2.2]octyltriazoles are potent and selective 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1) inhibitors with excellent pharmacokinetic profiles. 相似文献
19.
Sutin L Andersson S Bergquist L Castro VM Danielsson E James S Henriksson M Johansson L Kaiser C Flyrén K Williams M 《Bioorganic & medicinal chemistry letters》2007,17(17):4837-4840
2,5,5-Trisubstituted oxazolones were identified as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The synthesis, structure-activity relationship and metabolic stability of these compounds are presented. 相似文献
20.
《Bioorganic & medicinal chemistry letters》2014,24(9):2137-2140
The discovery of a novel series of cyclopenta[b]furans as CCR2 inhibitors is discussed. This series has excellent CCR2 potency and PK characteristics, and good cardiovascular safety. 相似文献