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1.
Rémi Patouret Christelle Doebelin Ruben D. Garcia-Ordonez Mi Ra Chang Claudia Ruiz Michael D. Cameron Patrick R. Griffin Theodore M. Kamenecka 《Bioorganic & medicinal chemistry letters》2018,28(7):1178-1181
Crystallography has identified stearic acid, ALRT 1550 and ATRA as ligands that bind RORβ, however, none of these molecules represent good starting points to develop optimized small molecule modulators. Recently, Compound 1 was identified as a potent dual RORβ and RORγ inverse agonist with no activity towards RORα (Fig. 1). To our knowledge, this is one of only two small molecule RORβ inverse agonists identified in the primary literature from a tractable chemical series and represents an ideal starting point from which to design RORβ-selective modulators. Herein we describe our SAR optimization efforts that led to a series of potent neutral antagonists of RORβ. 相似文献
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Alexey Rivkin Sean P. Ahearn Stephanie M. Chichetti Christopher L. Hamblett Yudith Garcia Michelle Martinez Jed L. Hubbs Michael H. Reutershan Matthew H. Daniels Phieng Siliphaivanh Karin M. Otte Chaomin Li Andrew Rosenau Laura M. Surdi Joon Jung Bethany L. Hughes Jamie L. Crispino George N. Nikov Richard E. Middleton Christopher M. Moxham Mark S. Shearman 《Bioorganic & medicinal chemistry letters》2010,20(7):2279-2282
The development of a novel series of purines as γ-secretase modulators for potential use in the treatment of Alzheimer’s disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based γ-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Αβ42 in an APP-YAC transgenic mouse model. 相似文献
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Daniel Oehlrich Frederik J.R. Rombouts Didier Berthelot François P. Bischoff Michel A.J. De Cleyn Libuse Jaroskova Gregor Macdonald Marc Mercken Michel Surkyn Andrés A. Trabanco Gary Tresadern Sven Van Brandt Adriana I. Velter Tongfei Wu Harrie J.M. Gijsen 《Bioorganic & medicinal chemistry letters》2013,23(17):4794-4800
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer’s drug which demonstrated high in vitro and in vivo potency against Aβ42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series. 相似文献
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Herberich B Jackson C Wurz RP Pettus LH Sherman L Liu Q Henkle B Saris CJ Wong LM Chmait S Lee MR Mohr C Hsieh F Tasker AS 《Bioorganic & medicinal chemistry letters》2012,22(2):1226-1229
Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles. 相似文献
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Gilles Ouvry Franck Bihl Claire Bouix-Peter Olivier Christin Claire Defoin-Platel Sophie Deret Christophe Feret David Froude Feriel Hacini-Rachinel Craig S. Harris Catherine Hervouet Guillaume Lafitte Anne-Pascale Luzy Branislav Musicki Danielle Orfila Veronique Parnet Coralie Pascau Jonathan Pascau Laurent F. Hennequin 《Bioorganic & medicinal chemistry letters》2018,28(8):1269-1273
Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model. 相似文献
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Hakamata W Ishikawa R Ushijima Y Tsukagoshi T Tamura S Hirano T Nishio T 《Bioorganic & medicinal chemistry letters》2012,22(1):62-64
5-Thiazoleacetamide derivatives of AR122 and AR125 were screened as α-glucosidase inhibitors by in silico high-throughput screening from commercial drug-like small compound libraries. Inhibition of α-glucosidase with AR122 and AR125 is time dependent: with no preincubation, AR122 and AR125 are relatively moderate inhibitors, but interestingly, after a 120 min incubation, they were 50-fold more potent (AR122: IC(50)=2.47 μM and AR125: IC(50)=27.1 μM). Plots of ln [residual α-glucosidase activity %] versus preincubation time show a pseudo-first order kinetics for both inhibitors. Through dialysis of enzyme-inhibitor complexes, no activity recovery was shown. These results suggest that AR122 and AR125 constitute a new class of noncarbohydrate mimetic inhibitor with an irreversible mechanism. 相似文献
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Christian Gege Maxwell D. Cummings Michael Albers Olaf Kinzel Gerald Kleymann Thomas Schlüter Christoph Steeneck Marina I. Nelen Cindy Milligan John Spurlino Xiaohua Xue Kristi Leonard James P. Edwards Anne Fourie Steven D. Goldberg Thomas Hoffmann 《Bioorganic & medicinal chemistry letters》2018,28(9):1446-1455
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Kimberly M. Lovell Andrew S. Felts Alice L. Rodriguez Daryl F. Venable Hyekyung P. Cho Ryan D. Morrison Frank W. Byers J. Scott Daniels Colleen M. Niswender P. Jeffrey Conn Craig W. Lindsley Kyle A. Emmitte 《Bioorganic & medicinal chemistry letters》2013,23(13):3713-3718
Development of SAR in an N-acyl-N′-arylpiperazine series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. Characterization of selected compounds in protein binding assays was used to aid in selecting VU0469650 for further profiling in ancillary pharmacology assays and pharmacokinetic studies. VU0469650 demonstrated an excellent selectivity profile and good exposure in both plasma and brain samples following intraperitoneal dosing in rats. 相似文献
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Yoshiyuki Fukase Ayumu Sato Yoshihide Tomata Atsuko Ochida Mitsunori Kono Kazuko Yonemori Keiko Koga Toshitake Okui Masashi Yamasaki Yasushi Fujitani Hideyuki Nakagawa Ryoukichi Koyama Masaharu Nakayama Robert Skene Bi-Ching Sang Isaac Hoffman Junya Shirai Satoshi Yamamoto 《Bioorganic & medicinal chemistry》2018,26(3):721-736
Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure–activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed. 相似文献
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Istrate MA Spicer TP Wang Y Bernard JA Helvering LM Bocchinfuso WP Richardson TI Zink R Kumar N Montrose-Rafizadeh C Dodge J Hodder P Griffin PR 《Journal of biomolecular screening》2011,16(2):183-191
The retinoid acid receptor-related orphan receptors (RORs) represent important targets for the treatment of metabolic and immune disorders. Here the authors describe the application of AlphaScreen(?) technology to develop a high-throughput screening (HTS)-compatible assay to facilitate the discovery of RORα modulators. Using the ligand binding domain (LBD) of RORα and a peptide derived from the NR1 box of the nuclear receptor coactivator PGC-1α, a 384-well format assay was developed exhibiting high sensitivity, requiring only low nanomolar concentration of reagents. Recently, it was shown that oxysterols such as 7α-hydroxycholesterol (7α-OHC) function as modulators of the RORs. In this assay, 7α-OHC produced a concentration-response curve with an EC(50) of 162 nM, a Z' factor of 0.6, and a signal-to-background (S/B) ratio of 4.2, demonstrating that the assay is HTS compatible. Validation of the assay was afforded by screening against the Sigma LOPAC1280? library in a 384-well format. In summary, the results presented here demonstrate that this assay can be used to screen large chemical libraries to discover novel modulators of RORα. 相似文献
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François P. Bischoff Adriana Ingrid Velter Garrett Minne Serge Pieters Didier Berthelot Michel De Cleyn Harrie J.M. Gijsen Gregor Macdonald Michel Surkyn Sven Van Brandt Yves Van Roosbroeck Chiara Zavattaro Marc Mercken Nigel Austin Deborah Dhuyvetter Herman Borghys Ishtiyaque Ahmad Swapan Kumar Samanta 《Bioorganic & medicinal chemistry letters》2019,29(14):1737-1745
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile. 相似文献
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David Marcoux Lan-Ying Qin Zheming Ruan Qing Shi Qian Ruan Carolyn Weigelt Hongchen Qiu Gary Schieven John Hynes Rajeev Bhide Michael Poss Joseph Tino 《Bioorganic & medicinal chemistry letters》2017,27(13):2849-2853
Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined. 相似文献
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《Bioorganic & medicinal chemistry letters》2014,24(10):2267-2272
The discovery and SAR of a novel series of potent and selective PPARα antagonists are herein described. Exploration of replacements for the labile acyl sulfonamide linker led to a biaryl sulfonamide series of which compound 33 proved to be suitable for further profiling in vivo. Compound 33 demonstrated excellent potency, selectivity against other nuclear hormone receptors, and good pharmacokinetics in mouse. 相似文献
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Fischer C Zultanski SL Zhou H Methot JL Shah S Nuthall H Hughes BL Smotrov N Hill A Szewczak AA Moxham CM Bays N Middleton RE Munoz B Shearman MS 《Bioorganic & medicinal chemistry letters》2012,22(9):3140-3146
Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aβ42 IC(50) in cell-based assays and reduced affinity for the hERG channel. 相似文献
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《生物化学与生物物理学报:疾病的分子基础》2019,1865(12):165537
Transforming growth factor-β (TGF-β) signaling plays fundamental roles in the development and homeostasis of somatic cells. Dysregulated TGF-β signaling contributes to cancer progression and relapse to therapies by inducing epithelial-to-mesenchymal transition (EMT), enriching cancer stem cells, and promoting immunosuppression. Although many TGF-β-regulated genes have been identified, only a few datasets were obtained by next-generation sequencing. In this study, we performed RNA-sequencing analysis of MCF10A cells and identified 1166 genes that were upregulated and 861 genes that were downregulated by TGF-β. Gene set enrichment analysis revealed that focal adhesion and metabolic pathways were the top enriched pathways of the up- and downregulated genes, respectively. Genes in these pathways also possess significant predictive value for renal cancers. Moreover, we confirmed that TGF-β induced expression of MICAL1 and 2, and the histone demethylase, KDM7A, and revealed their regulatory roles on TGF-β-induced cell migration. We also show a critical effect of KDM7A in regulating the acetylation of H3K27 on TGF-β-induced genes. In sum, this study identified novel effectors that mediate the pro-migratory role of TGF-β signaling, paving the way for future studies that investigate the function of MICAL family members in cancer and the novel epigenetic mechanisms downstream TGF-β signaling. 相似文献
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Yann Lamotte Paul Martres Nicolas Faucher Alain Laroze Didier Grillot Nicolas Ancellin Yannick Saintillan Véronique Beneton Robert T. Gampe 《Bioorganic & medicinal chemistry letters》2010,20(4):1399-1404
Starting from the structure of Telmisartan, a new series of potent and selective PPARγ modulators was identified. The synthesis, in vitro and in vivo evaluation of the most potent compounds are reported and the X-ray structure of compound 7b bound to the PPARγ ligand binding domain is described. 相似文献
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Junya Shirai Yoshihide Tomata Mitsunori Kono Atsuko Ochida Yoshiyuki Fukase Ayumu Sato Shinichi Masada Tetsuji Kawamoto Kazuko Yonemori Ryoukichi Koyama Hideyuki Nakagawa Masaharu Nakayama Keiko Uga Akira Shibata Keiko Koga Toshitake Okui Mikio Shirasaki Robert Skene Satoshi Yamamoto 《Bioorganic & medicinal chemistry》2018,26(2):483-500