共查询到20条相似文献,搜索用时 15 毫秒
1.
Link JT Sorensen BK Patel J Emery M Grynfarb M Goos-Nilsson A 《Bioorganic & medicinal chemistry letters》2004,14(9):2209-2212
A new class of selective nonsteroidal glucocorticoid receptor modulators typified by N-[3-[benzyl-(4-chloro-2-fluoro-benzyl)-amino]-2-methyl-phenyl]-methanesulfonamide 19 has been discovered. 相似文献
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James E. Sheppeck John L. Gilmore Hai-Yun Xiao T.G. Murali Dhar David Nirschl Arthur M. Doweyko Jack S. Sack Martin J. Corbett Mary F. Malley Jack Z. Gougoutas Lorraine Mckay Mark D. Cunningham Sium F. Habte John H. Dodd Steven G. Nadler John E. Somerville Joel C. Barrish 《Bioorganic & medicinal chemistry letters》2013,23(19):5442-5447
Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure. 相似文献
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Tasler S Kraus J Wuzik A Müller O Aschenbrenner A Cubero E Pascual R Quintana-Ruiz JR Dordal A Mercè R Codony X 《Bioorganic & medicinal chemistry letters》2007,17(22):6224-6229
Based on a pharmacophore alignment on a 5-HT(6) ligand applying 4SCan technology, a new lead series was identified and further structurally investigated. K(i)s down to 8 nM were achieved. 相似文献
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A nonsteroidal glucocorticoid receptor antagonist 总被引:4,自引:0,他引:4
Miner JN Tyree C Hu J Berger E Marschke K Nakane M Coghlan MJ Clemm D Lane B Rosen J 《Molecular endocrinology (Baltimore, Md.)》2003,17(1):117-127
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Chang-Fong J Rangisetty JB Dukat M Setola V Raffay T Roth B Glennon RA 《Bioorganic & medicinal chemistry letters》2004,14(8):1961-1964
An investigation of the structure-affinity relationships for the binding of 4-(N,N-dimethylaminomethyl)-N(9)-arylsulfonyl-9H-1,2,3,4-tetrahydrocarbazoles (conformationally-constrained analogues of the benzenesulfonyltryptamine 5-HT(6) antagonist MS-245) at human 5-HT(6) receptors revealed that various arylsulfonyl substituents are tolerated and that the 4-(N,N-dimethylaminomethyl) group is not required for binding. In particular, N(9)-(4-aminobenzenesulfonyl)-9H-1,2,3,4-tetrahydrocarbazole (20, K(i)=29 nM) was found to bind with high affinity and represents the first member of a new structural class of agents with 5-HT(6) antagonist properties (pA(2)=7.0; cAMP hydrolysis assay). 相似文献
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Takahashi H Bekkali Y Capolino AJ Gilmore T Goldrick SE Nelson RM Terenzio D Wang J Zuvela-Jelaska L Proudfoot J Nabozny G Thomson D 《Bioorganic & medicinal chemistry letters》2006,16(6):1549-1552
We report the discovery of a novel class of glucocorticoid receptor (GR) ligands based on 1,2-dihydroquinoline molecular scaffold. The compounds exhibit good GR binding affinity and selectivity profile against other nuclear hormone receptors. 相似文献
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Tu N Link JT Sorensen BK Emery M Grynfarb M Goos-Nilsson A Nguyen B 《Bioorganic & medicinal chemistry letters》2004,14(16):4179-4183
Bile acid conjugates of a selective nonsteroidal glucocorticoid receptor modulator were prepared and evaluated. Potent GR binding conjugates that showed improved metabolic stability were discovered. However, cellular potency and pharmacokinetics were not substantially improved. 相似文献
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Peräkylä M Malinen M Herzig KH Carlberg C 《Molecular endocrinology (Baltimore, Md.)》2005,19(8):2060-2073
The seco-steroid 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] is a promising drug candidate due to its pleiotropic function including the regulation of calcium homeostasis, bone mineralization and cellular proliferation, differentiation, and apoptosis. We report here a novel class of nonsteroidal compounds, represented by the bis-aromatic molecules CD4409, CD4420, and CD4528, as ligands of the 1alpha,25(OH)2D3 receptor (VDR). Taking the known diphenylmethane derivative LG190178 as a reference, this study provides molecular evaluation of the interaction of nonsteroidal ligands with the VDR. All four nonsteroidal compounds were shown to induce VDR-retinoid X receptor heterodimer complex formation on a 1alpha,25(OH)2D3 response element, stabilize the agonistic conformation of the VDR ligand-binding domain, enable the interaction of VDR with coactivator proteins and contact with their three hydroxyl groups the same residues within the ligand-binding pocket of the VDR as 1alpha,25(OH)2D3. Molecular dynamics simulations demonstrated that all four nonsteroidal ligands take a shape within the ligand-binding pocket of the VDR that is very similar to that of the natural ligand. CD4528 is mimicking the natural hormone best and was found to be in vitro at least five times more potent than LG190178. In living cells, CD4528 was only two times less potent than 1alpha,25(OH)2D3 and induced mRNA expression of the VDR target gene CYP24 in a comparable fashion. At a noncalcemic dose of 150 microg/kg, CD4528 showed in vivo a clear induction of CYP24 expression and therefore may be used as a lead compound for the development of therapeutics against psoriasis, osteoporosis, and cancer. 相似文献
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Stefan Jaroch Markus Berger Christoph Huwe Konrad Krolikiewicz Hartmut Rehwinkel Heike Schäcke Norbert Schmees Werner Skuballa 《Bioorganic & medicinal chemistry letters》2010,20(19):5835-5838
The dissociated glucocorticoid receptor (GR) agonist ZK 216348 is rendered GR-selective over other nuclear hormone receptors through replacing the methylbenzoxazine with a quinoline moiety. Compounds were shown to be efficacious in cell assays with respect to inflammation endpoints, along with reduced activity in a transactivation assay, hinting at an improved therapeutic window over corticosteroids. 相似文献
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Bungard CJ Hartman GD Manikowski JJ Perkins JJ Bai C Brandish PE Euler DH Hershey JC Schmidt A Fang Y Norcross RT Rushmore TH Thompson CD Meissner RS 《Bioorganic & medicinal chemistry》2011,19(24):7374-7386
A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists. Oxidative N-dealkylation was blocked in a new series of compounds, however oxidation alone was capable of producing full agonist metabolites. Incorporation of an ortho-primary amide and utilization of fluorine to modulate agonism afforded partial agonist MK-5932. Synthesis of the major metabolites of MK-5932 using bioreactor technology revealed that no significant GR-active metabolites were formed. Orally administered MK-5932 displayed anti-inflammatory efficacy in a Rat Oxazolone-induced chronic dermatitis model, while sparing plasma insulin. 相似文献
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Hudson AR Higuchi RI Roach SL Adams ME Vassar A Syka PM Mais DE Miner JN Marschke KB Zhi L 《Bioorganic & medicinal chemistry letters》2011,21(6):1697-1700
A series of tetrahydroquinoline derivatives were synthesized and profiled for their ability to act as glucocorticoid receptor selective modulators. Structure-activity relationships of the tetrahydroquinoline B-ring lead to the discovery of orally available GR-selective agonists with high in vivo activity. 相似文献
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Markus Berger Hartmut Rehwinkel Norbert Schmees Heike Schäcke Karl Edman Lisa Wissler Andreas Reichel Stefan Jaroch 《Bioorganic & medicinal chemistry letters》2017,27(3):437-442
We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro. 相似文献
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Marshall DR Rodriguez G Thomson DS Nelson R Capolina A 《Bioorganic & medicinal chemistry letters》2007,17(2):315-319
Alpha-methyltryptamine sulfonamides were identified as human glucocorticoid receptor (hGR) ligands in an ultra high throughput screening (UHTS) campaign. Described will be the hit-to-lead activities, including parallel and single point analog synthesis to map the scaffold. Ligands were identified that exhibited 30 nM binding to hGR. The SAR and selectivity of these compounds will be discussed. 相似文献
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Zhao S Shen Y van Oeveren A Marschke KB Zhi L 《Bioorganic & medicinal chemistry letters》2008,18(11):3431-3435
A novel oxachrysenone series (2) of nonsteroidal selective androgen receptor modulators (SARM) was developed based on the 6-aryl-2-quinolinones (1). Synthesis and preliminary SAR results based on in vitro assays are discussed. In the cotransfection assay, lead compound 5d showed AR agonist activity more potent than dihydrotestosterone (DHT), whereas compound 17b was a potent antagonist similar to bicalutamide. 相似文献
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Farmer LJ Zhi L Jeong S Lamph WW Osburn DL Croston G Flatten KS Heyman RA Nadzan AM 《Bioorganic & medicinal chemistry letters》2003,13(2):261-264
A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RAR's EC(50)=17-59 nM; RXR's EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226. 相似文献
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Jiang W Fiordeliso JJ Allan G Linton O Tannenbaum P Xu J Zhu P Gunnet J Demarest K Lundeen S Sui Z 《Bioorganic & medicinal chemistry letters》2007,17(5):1471-1474
Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-diabetic activities. For glucocorticoid receptor (GR) program, we sought an unexplored, synthetically accessible phosphorus-containing steroidal mimetic of mifepristone, suitable for parallel synthesis of analogues. One compound 4a, with high oral bioavailability (59%) in rat, exhibited functional antagonism of GR in oral glucose tolerance test (OGTT). Thus this series of compounds might be potentially useful for the treatment of type II diabetes. 相似文献
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Takahashi H Bekkali Y Capolino AJ Gilmore T Goldrick SE Kaplita PV Liu L Nelson RM Terenzio D Wang J Zuvela-Jelaska L Proudfoot J Nabozny G Thomson D 《Bioorganic & medicinal chemistry letters》2007,17(18):5091-5095
We have recently reported the discovery of a novel class of glucocorticoid receptor (GR) antagonists, exemplified by 3, containing a 1,2-dihydroquinoline molecular scaffold. Further SAR studies of these antagonists uncovered chemical modifications conveying agonist functional activity to this series. These agonists exhibit good GR binding affinity and are selective against other nuclear hormone receptors. 相似文献