共查询到20条相似文献,搜索用时 31 毫秒
1.
Tizita Haimanot Admas Dr. Viachaslau Bernat Prof. Dr. Markus R. Heinrich Dr. Nuska Tschammer 《ChemMedChem》2016,11(6):575-584
The CXCR3 receptor, a class A G protein‐coupled receptor (GPCR), is involved in the regulation and trafficking of various immune cells. CXCR3 antagonists have been proposed to be beneficial for the treatment of a wide range of disorders including but not limited to inflammatory and autoimmune diseases. The structure‐based design of CXCR3 ligands remains, however, hampered by a lack of structural information describing in detail the interactions between an allosteric ligand and the receptor. We designed and synthesized photoactivatable probes for the structural and functional characterization, using photoaffinity labeling followed by mass spectrometry, of the CXCR3 allosteric binding pocket of AMG 487 and RAMX3, two potent and selective CXCR3 negative allosteric modulators. Photoaffinity labeling is a common approach to elucidate binding modes of small‐molecule ligands of GPCRs through the aid of photoactivatable probes that convert to extremely reactive intermediates upon photolysis. The photolabile probe N‐[({1‐[3‐(4‐ethoxyphenyl)‐4‐oxo‐3,4‐dihydropyrido[2,3‐d]pyrimidin‐2‐yl]ethyl}‐2‐[4‐fluoro‐3‐(trifluoromethyl)phenyl]‐N‐{1‐[4‐(3‐(trifluoromethyl)‐3H‐diazirin‐3‐yl]benzyl}piperidin‐4‐yl)methyl]acetamide ( 10 ) showed significant labeling of the CXCR3 receptor (80 %) in a [3H]RAMX3 radioligand displacement assay. Compound 10 will serve as an important tool compound for the detailed investigation of the binding pocket of CXCR3 by mass spectrometry. 相似文献
2.
Ligand‐Biased and Probe‐Dependent Modulation of Chemokine Receptor CXCR3 Signaling by Negative Allosteric Modulators
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Dr. Viachaslau Bernat Regine Brox Prof. Dr. Markus R. Heinrich Dr. Yves P. Auberson Dr. Nuska Tschammer 《ChemMedChem》2015,10(3):566-574
Over the last decade, functional selectivity (or ligand bias) has evolved from being a peculiar phenomenon to being recognized as an essential feature of synthetic ligands that target G protein‐coupled receptors (GPCRs). The CXC chemokine receptor 3 (CXCR3) is an outstanding platform to study various aspects of biased signaling, because nature itself uses functional selectivity to manipulate receptor signaling. At the same time, CXCR3 is an attractive therapeutic target in the treatment of autoimmune diseases and cancer. Herein we report the discovery of an 8‐azaquinazolinone derivative (N‐{1‐[3‐(4‐ethoxyphenyl)‐4‐oxo‐3,4‐dihydropyrido[2,3‐d]pyrimidin‐2‐yl]ethyl}‐4‐(4‐fluorobutoxy)‐N‐[(1‐methylpiperidin‐4‐yl)methyl]butanamide, 1 b ) that can inhibit CXC chemokine 11 (CXCL11)‐dependent G protein activation over β‐arrestin recruitment with 187‐fold selectivity. This compound also demonstrates probe‐dependent activity, that is, it inhibits CXCL11‐ over CXCL10‐mediated G protein activation with 12‐fold selectivity. Together with a previously reported biased negative allosteric modulator from our group, the present study provides additional information on the molecular requirements for allosteric modulation of CXCR3. 相似文献
3.
Synthesis and Biological Evaluation of New Triazolo‐ and Imidazolopyridine RORγt Inverse Agonists
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Dr. Samuel Hintermann Dr. Christine Guntermann Dr. Henri Mattes Dr. David A. Carcache Dr. Juergen Wagner Dr. Anna Vulpetti Dr. Andreas Billich Dr. Janet Dawson Dr. Klemens Kaupmann Dr. Joerg Kallen Dr. Rowan Stringer Dr. David Orain 《ChemMedChem》2016,11(24):2640-2648
4.
Exploration of Sulfur‐Containing Analogues for Imaging Vesicular Acetylcholine Transporter in the Brain
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Dr. Zonghua Luo Dr. Hui Liu Dr. Hongjun Jin Dr. Jiwei Gu Dr. Yanbo Yu Dr. Kota Kaneshige Prof. Joel S. Perlmutter Prof. Stanley M. Parsons Prof. Zhude Tu 《ChemMedChem》2018,13(18):1978-1987
Sixteen new sulfur‐containing compounds targeting the vesicular acetylcholine transporter (VAChT) were synthesized and assessed for in vitro binding affinities. Enantiomers (?)‐(1‐(3‐hydroxy‐1,2,3,4‐tetrahydronaphthalen‐2‐yl)piperidin‐4‐yl)(4‐(methylthio)phenyl)methanone [(?)‐ 8 ] and (?)‐(4‐((2‐fluoroethyl)thio)phenyl)(1‐(3‐hydroxy‐1,2,3,4‐tetrahydronaph‐thalen‐2‐yl)piperidin‐4‐yl)methanone [(?)‐ 14 a ] displayed high binding affinities, with respective Ki values of 1.4 and 2.2 nm for human VAChT, moderate and high selectivity for human VAChT over σ1 (≈13‐fold) and σ2 receptors (>420‐fold). Radiosyntheses of (?)‐[11C] 8 and (?)‐[18F] 14 a were achieved using conventional methods. Ex vivo autoradiography and biodistribution studies in Sprague–Dawley rats indicated that both radiotracers have the capacity to penetrate the blood–brain barrier, with high initial brain uptake at 5 min and rapid washout. The striatal region had the highest accumulation for both radiotracers. Pretreating the rats with the VAChT ligand (?)‐vesamicol decreased brain uptake for both radiotracers. Pretreating the rats with the σ1 ligand YUN‐122 (N‐(4‐benzylcyclohexyl)‐2‐(2‐fluorophenyl)acetamide) also decreased brain uptake, suggesting these two radiotracers also bind to the σ1 receptor in vivo. The microPET study of (?)‐[11C] 8 in the brain of a non‐human primate showed high striatal accumulation that peaked quickly and washed out rapidly. Although preliminary results indicated these two sulfur‐containing radiotracers have high binding affinities for VAChT with rapid washout kinetics from the striatum, their σ1 receptor binding properties limit their potential as radiotracers for quantifying VAChT in vivo. 相似文献
5.
Nicolas Lassauque Giancarlo Franci Walter Leitner 《Advanced Synthesis \u0026amp; Catalysis》2009,351(18):3133-3138
At room temperature, nickel catalysts based on the new phosphoramidite (11bR)‐N‐[(S)‐1‐(naphthalen‐1‐yl)ethyl]‐N‐[(S)‐1‐(naphthalen‐2‐yl)ethyl]dinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepin‐4‐amine provide excellent selectivities for 3‐arylbut‐1‐enes (93–99%) with high enantioselectivities (90–95% ee) and TOFs (up to 8300 h−1) in the hydrovinylation of electron‐rich and electron‐poor vinylarenes. Within a few minutes, useful chiral building blocks and intermediates can be synthesized using this practical catalytic system. 相似文献
6.
Isaac Zentner Luz‐Jeannette Sierra Ayesha K. Fraser Lina Maciunas Marie K. Mankowski Dr. Andrei Vinnik Dr. Peter Fedichev Roger G. Ptak Dr. Julio Martín‐García Dr. Simon Cocklin 《ChemMedChem》2013,8(3):426-432
The development of drug resistance remains a critical problem for current HIV‐1 antiviral therapies, creating a need for new inhibitors of HIV‐1 replication. We previously reported on a novel anti‐HIV‐1 compound, N2‐(phenoxyacetyl)‐N‐[4‐(1‐piperidinylcarbonyl)benzyl]glycinamide ( 14 ), that binds to the highly conserved phosphatidylinositol (4,5)‐bisphosphate (PI(4,5)P2) binding pocket of the HIV‐1 matrix (MA) protein. In this study, we re‐evaluate the hits from the virtual screen used to identify compound 14 and test them directly in an HIV‐1 replication assay using primary human peripheral blood mononuclear cells. This study resulted in the identification of three new compounds with antiviral activity; 2‐(4‐{[3‐(4‐fluorophenyl)‐1,2,4‐oxadiazol‐5‐yl]methyl})‐1‐piperazinyl)‐N‐(4‐methylphenyl)acetamide ( 7 ), 3‐(2‐ethoxyphenyl)‐5‐[[4‐(4‐nitrophenyl)piperazin‐1‐yl]methyl]‐1,2,4‐oxadiazole ( 17 ), and N‐[4‐ethoxy‐3‐(1‐piperidinylsulfonyl)phenyl]‐2‐(imidazo[2,1‐b][1,3]thiazol‐6‐yl)acetamide ( 18 ), with compound 7 being the most potent of these hits. Mechanistic studies on 7 demonstrated that it directly interacts with and functions through HIV‐1 MA. In accordance with our drug target, compound 7 competes with PI(4,5)P2 for MA binding and, as a result, diminishes the production of new virus. Mutation of residues within the PI(4,5)P2 binding site of MA decreased the antiviral effect of compound 7 . Additionally, compound 7 displays a broadly neutralizing anti‐HIV activity, with IC50 values of 7.5–15.6 μM for the group M isolates tested. Taken together, these results point towards a novel chemical probe that can be used to more closely study the biological role of MA and could, through further optimization, lead to a new class of anti‐HIV‐1 therapeutics. 相似文献
7.
Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist,Preclinical Candidate for the Topical Treatment of Psoriasis
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Dr. Gilles Ouvry Dr. Nicolas Atrux‐Tallau Dr. Franck Bihl Aline Bondu Dr. Claire Bouix‐Peter Isabelle Carlavan Olivier Christin Marie‐Josée Cuadrado Dr. Claire Defoin‐Platel Dr. Sophie Deret Denis Duvert Christophe Feret Mathieu Forissier Dr. Jean‐François Fournier David Froude Dr. Fériel Hacini‐Rachinel Dr. Craig Steven Harris Dr. Catherine Hervouet Dr. Hélène Huguet Guillaume Lafitte Dr. Anne‐Pascale Luzy Dr. Branislav Musicki Danielle Orfila Benjamin Ozello Coralie Pascau Jonathan Pascau Véronique Parnet Guillaume Peluchon Romain Pierre Dr. David Piwnica Dr. Catherine Raffin Patricia Rossio Delphine Spiesse Dr. Nathalie Taquet Dr. Etienne Thoreau Rodolphe Vatinel Dr. Emmanuel Vial Dr. Laurent François Hennequin 《ChemMedChem》2018,13(4):321-337
With possible implications in multiple autoimmune diseases, the retinoic acid receptor‐related orphan receptor RORγ has become a sought‐after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N‐(2,4‐dimethylphenyl)‐N‐isobutyl‐2‐oxo‐1‐[(tetrahydro‐2H‐pyran‐4‐yl)methyl]‐2,3‐dihydro‐1H‐benzo[d]imidazole‐5‐sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL‐23‐induced mouse skin inflammation model. 相似文献
8.
Pramipexole Derivatives as Potent and Selective Dopamine D3 Receptor Agonists with Improved Human Microsomal Stability
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Dr. Jianyong Chen Dr. Cheng Jiang Prof. Beth Levant Dr. Xiaoqin Li Dr. Ting Zhao Dr. Bo Wen Dr. Ruijuan Luo Prof. Duxin Sun Prof. Shaomeng Wang 《ChemMedChem》2014,9(12):2653-2660
Herein we report the synthesis and evaluation of a series of new pramipexole derivatives as highly potent and selective agonists of the dopamine‐3 (D3) receptor. A number of these new compounds bind to the D3 receptor with sub‐nanomolar affinity and show excellent selectivity (>10 000) for the D3 receptor over the D1 and D2 receptors. For example, compound 23 (N‐(cis‐3‐(2‐(((S)‐2‐amino‐4,5,6,7‐tetrahydrobenzo[d]thiazol‐6‐yl)(propyl)amino)ethyl)‐3‐hydroxycyclobutyl)‐3‐(5‐methyl‐1,2,4‐oxadiazol‐3‐yl)benzamide) binds to the D3 receptor with a Ki value of 0.53 nM and shows a selectivity of >20 000 over the D2 and D1 receptors in the binding assays using a rat brain preparation. It has excellent stability in human liver microsomes. Moreover, in vitro functional assays showed it to be a full agonist for the human D3 receptor. 相似文献
9.
Bioorthogonally Applicable Fluorescence Deactivation Strategy for Receptor Kinetics Study and Theranostic Pretargeting Approaches
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Steffen van der Wal Clarize M. de Korne Laurens G. L. Sand Danny M. van Willigen Prof. Pancras C. W. Hogendoorn Dr. Karoly Szuhai Dr. Fijs W. B. van Leeuwen Dr. Tessa Buckle 《Chembiochem : a European journal of chemical biology》2018,19(16):1758-1765
The availability of a receptor for theranostic pretargeting approaches was assessed by use of a new click‐chemistry‐based deactivatable fluorescence‐quenching concept. The efficacy was evaluated in a cell‐based model system featuring both membranous (available) and internalized (unavailable) receptor fractions of the clinically relevant receptor chemokine receptor 4 (CXCR4). Proof of concept was achieved with a deactivatable tracer consisting of a CXCR4‐specific peptide functionalized with a Cy5 dye bearing a chemoselective azide handle (N3‐Cy5‐AcTZ14011). Treatment with a Cy7 quencher dye (Cy7‐DBCO) resulted in optically silent Cy7‐[click]‐Cy5‐AcTZ14011. In situ, a >90 % FRET‐based reduction of the signal intensity of N3‐Cy5‐AcTZ14011 [KD=(222.4±25.2) nm ] was seen within minutes after quencher addition. In cells, discrimination between the membranous and the internalized receptor fraction could be achieved through quantitative assessment of quenching/internalization kinetics. Similar evaluation of an activatable tracer variant based on the same targeting moiety (Cy5‐S‐S‐Cy3‐AcTZ14011) was unsuccessful in vitro. As such, using the described deactivatable approach to screen membrane receptors and their applicability in receptor‐(pre‐)targeted theranostics can become straightforward. 相似文献
10.
Automated Synthesis of (rac)‐, (R)‐, and (S)‐[18F]Epifluorohydrin and Their Application for Developing PET Radiotracers Containing a 3‐[18F]Fluoro‐2‐hydroxypropyl Moiety
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Dr. Tomoteru Yamasaki Yiding Zhang Wakana Mori Dr. Masayuki Hanyu Katsushi Kumata Akiko Hatori Dr. Lin Xie Nobuki Nengaki Prof. Dr. Ming‐Rong Zhang 《ChemMedChem》2018,13(16):1723-1731
To introduce the 3‐[18F]fluoro‐2‐hydroxypropyl moiety into positron emission tomography (PET) radiotracers, we performed automated synthesis of (rac)‐, (R)‐, and (S)‐[18F]epifluorohydrin ([18F] 1 ) by nucleophilic displacement of (rac)‐, (R)‐, or (S)‐glycidyl tosylate with 18F? and purification by distillation. The ring‐opening reaction of (R)‐ or (S)‐[18F] 1 with phenol precursors gave enantioenriched [18F]fluoroalkylated products without racemisation. We then synthesised (rac)‐, (R)‐, and (S)‐ 2‐{5‐[4‐(3‐[18F]fluoro‐2‐hydroxypropoxy)phenyl]‐2‐oxobenzo[d]oxazol‐3(2H)‐yl}‐N‐methyl‐N‐phenylacetamide ([18F] 6 ) as novel radiotracers for the PET imaging of translocator protein (18 kDa) and showed that (R)‐ and (S)‐[18F] 6 had different radioactivity uptake in mouse bone and liver. Thus, (rac)‐, (R)‐, and (S)‐[18F] 1 are effective radiolabelling reagents and can be used to develop PET radiotracers by examining the effects of chirality on their in vitro binding affinities and in vivo behaviour. 相似文献
11.
From Type I to Type II: Design,Synthesis, and Characterization of Potent Pyrazin‐2‐ones as DFG‐Out Inhibitors of PDGFRβ
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Eugen Bethke Boris Pinchuk Christian Renn Lydia Witt Dr. Joachim Schlosser Prof. Dr. Christian Peifer 《ChemMedChem》2016,11(24):2664-2674
Reversible protein kinase inhibitors that bind in the ATP cleft can be classified as type I or type II binders. Of these, type I inhibitors address the active form, whereas type II inhibitors typically lock the kinase in an inactive form. At the molecular level, the conformation of the flexible activation loop holding the key DFG motif controls access to the ATP site, thereby determining an active or inactive kinase state. Accordingly, type I and type II kinase inhibitors bind to so‐called DFG‐in or DFG‐out conformations, respectively. Based on our former study on highly selective platelet‐derived growth factor receptor β (PDGFRβ) pyrazin‐2‐one type I inhibitors, we expanded this scaffold toward the deep pocket, yielding the highly potent and effective type II inhibitor 5 (4‐[(4‐methylpiperazin‐1‐yl)methyl]‐N‐[3‐[[6‐oxo‐5‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrazin‐3‐yl]methyl]phenyl]benzamide). In vitro characterization, including selectivity panel data from activity‐based assays (300 kinases) and affinity‐based assays (97 kinases) of these PDGFRβ type I ( 1 ; 5‐(4‐hydroxy‐3‐methoxy‐phenyl)‐3‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrazin‐2‐one) and II ( 5 ) inhibitors showing the same pyrazin‐2‐one chemotype are compared. Implications are discussed regarding the data for selectivity and efficacy of type I and type II ligands. 相似文献
12.
Structural Optimization of Berberine as a Synergist to Restore Antifungal Activity of Fluconazole against Drug‐Resistant Candida albicans
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Hong Liu Liang Wang Yan Li Jiang Liu Maomao An Shaolong Zhu Yongbing Cao Zhihui Jiang Mingzhu Zhao Zhan Cai Li Dai Tingjunhong Ni Wei Liu Simin Chen Changqing Wei Chengxu Zang Shujuan Tian Prof. Jingyu Yang Prof. Dr. Chunfu Wu Prof. Dr. Dazhi Zhang Prof. Dr. Hua Liu Prof. Yuanying Jiang 《ChemMedChem》2014,9(1):207-216
We have conducted systematic structural modification, deconstruction, and reconstruction of the berberine core with the aim of lowering its cytotoxicity, investigating its pharmacophore, and ultimately, seeking novel synergistic agents to restore the effectiveness of fluconazole against fluconazole‐resistant Candida albicans. A structure–activity relationship study of 95 analogues led us to identify the novel scaffold of N‐(2‐(benzo[d][1,3]dioxol‐5‐yl)ethyl)‐2‐(substituted phenyl)acetamides 7 a – l , which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7 d (N‐(2‐(benzo[d][1,3]dioxol‐5‐yl)ethyl)‐2‐(2‐fluorophenyl)acetamide) significantly decreased the MIC80 values of fluconazole from 128.0 μg mL?1 to 0.5 μg mL?1 against fluconazole‐resistant C. albicans and exhibited much lower levels of cytotoxicity than berberine toward human umbilical vein endothelial cells. 相似文献
13.
Yasemin Arslan Udum Hüseyin Bekir Yıldız Hacer Azak Elif Sahin Oktay Talaz Ali Çırpan Levent Toppare 《应用聚合物科学杂志》2014,131(17)
New π‐conjugated polymers containing dithieno(3,2‐b:2′,3′‐d)pyrrole (DTP) were successfully synthesized via electropolymerization. The effect of structural differences on the electrochemical and optoelectronic properties of the 4‐[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl]aniline (DTP–aryl–NH2), 10‐[4H‐dithiyeno(3,2‐b:2′,3′‐d)pirol‐4‐il]dekan‐1‐amine (DTP–alkyl–NH2), and 1,10‐bis[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl] decane (DTP–alkyl–DTP) were investigated. The corresponding polymers were characterized by cyclic voltammetry, NMR (1H‐NMR and 13C‐NMR), and ultraviolet–visible spectroscopy. Changes in the electronic nature of the functional groups led to variations in the electrochemical properties of the π‐conjugated systems. The electroactive polymer films revealed redox couples and exhibited electrochromic behavior. The replacement of the DTP–alkyl–DTP unit with DTP–aryl–NH2 and DTP–alkyl–NH2 resulted in a lower oxidation potential. Both the poly(10‐(4H‐Dithiyeno[3,2‐b:2′,3′‐d]pirol‐4‐il)dekan‐1‐amin) (poly(DTP–alkyl–NH2)) and poly(1,10‐bis(4H‐dithieno[3,2‐b:2′,3′‐d]pyrrol‐4‐yl) decane) (poly(DTP–alkyl–DTP)) films showed multicolor electrochromism and also fast switching times (<1 s) in the visible and near infrared regions. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40701. 相似文献
14.
[3H]UR‐DE257: Development of a Tritium‐Labeled Squaramide‐Type Selective Histamine H2 Receptor Antagonist
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Dr. Paul Baumeister Dr. Daniela Erdmann Sabrina Biselli Nicole Kagermeier Prof. Dr. Sigurd Elz Dr. Günther Bernhardt Prof. Dr. Armin Buschauer 《ChemMedChem》2015,10(1):83-93
A series of new piperidinomethylphenoxypropylamine‐type histamine H2 receptor (H2R) antagonists with different substituted “urea equivalents” was synthesized and characterized in functional in vitro assays. Based on these data as selection criteria, radiosynthesis of N‐[6‐(3,4‐dioxo‐2‐{3‐[3‐(piperidin‐1‐ylmethyl)phenoxy]propylamino}cyclobut‐1‐enylamino)hexyl]‐(2,3‐3H2)propionic amide ([3H]UR‐DE257) was performed. The radioligand (specific activity: 63 Ci mmol?1) had high affinity for human, rat, and guinea pig H2R (hH2R, Sf9 cells: Kd, saturation binding: 31 nM , kinetic studies: 20 nM ). UR‐DE257 revealed high H2R selectivity on membranes of Sf9 cells, expressing the respective hHxR subtype (Ki values: hH1R: >10 000 nM , hH2R: 28 nM , hH3R: 3800 nM , hH4R: >10 000 nM ). In spite of insurmountable antagonism, probably due to rebinding of [3H]UR‐DE257 to the H2R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H2R affinities in competition binding assays. 相似文献
15.
Pharmacophore‐Based Design of Novel Oxadiazoles as Selective Sphingosine‐1‐phosphate (S1P) Receptor Agonists with in vivo Efficacy
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Dr. Anna Quattropani Dr. Wolfgang H. B. Sauer Dr. Stefano Crosignani Jerome Dorbais Dr. Patrick Gerber Jerome Gonzalez Delphine Marin Dr. Mathilde Muzerelle Fanny Beltran Dr. Anthony Nichols Dr. Katrin Georgi Dr. Manfred Schneider Dr. Pierre‐Alain Vitte Valerie Eligert Laurence Novo‐Perez Jennifer Hantson Sebastien Nock Dr. Susanna Carboni Dr. Adriano Luis Soares de Souza Dr. Jean‐François Arrighi Dr. Ursula Boschert Dr. Agnes Bombrun 《ChemMedChem》2015,10(4):688-714
Sphingosine‐1‐phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure–activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five‐membered heterocycles, and the use of diverse 2,2′‐disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P1 agonist, N‐methyl‐N‐(4‐{5‐[2‐methyl‐2′‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 45 ), and a dual S1P1,5 agonist, N‐methyl‐N‐(3‐{5‐[2′‐methyl‐2‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 49 ), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head‐to‐head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan‐S1P receptor agonist, S1P1,5 agonist 49 demonstrated comparable efficacy while S1P1‐selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS. 相似文献
16.
Exploring the Active Conformation of Cyclohexane Carboxylate Positive Allosteric Modulators of the Type 4 Metabotropic Glutamate Receptor
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Dr. Xavier Rovira Dr. Youssef Harrak Dr. Ana Trapero Dr. Patricia González‐Bulnes Fanny Malhaire Dr. Jean‐Philippe Pin Dr. Cyril Goudet Dr. Jesús Giraldo Dr. Amadeu Llebaria 《ChemMedChem》2014,9(12):2685-2698
The active conformation of a family of metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulators (PAMs) with the cyclohexane 1,2‐dicarboxylic scaffold present in cis‐2‐(3,5‐dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041) was investigated by testing structurally similar six‐membered ring compounds that have a locked conformation. The norbornane and cyclohexane molecules designed as mGlu4 conformational probes and the enantiomers of the trans diastereomer were computationally characterized and tested in mGlu4 pharmacological assays. The results support a VU0155041 active conformation, with the chair cyclohexane having the aromatic amide substituent in an axial position and the carboxylate in an equatorial position. Moreover, the receptor displays enantiomeric discrimination of the chiral PAMs. The constructed pharmacophore characterized a highly constrained mGlu4 allosteric binding site, thus providing a step forward in structure‐based drug design for mGlu4 PAMs. 相似文献
17.
Evaluating p97 Inhibitor Analogues for Their Domain Selectivity and Potency against the p97–p47 Complex
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Dr. Chen‐Jie Fang Dr. Lin Gui Dr. Xiaoyi Zhang Derek R. Moen Dr. Kelin Li Dr. Kevin J. Frankowski Dr. Henry J. Lin Dr. Frank J. Schoenen Dr. Tsui‐Fen Chou 《ChemMedChem》2015,10(1):52-56
We previously found that p97 ATPase inhibitors 2‐(2‐amino‐1H‐benzo[d]imidazol‐1‐yl)‐N‐benzyl‐8‐methoxyquinazolin‐4‐amine ( ML240 ) and 2‐(2H‐benzo[b][1,4]oxazin‐4(3H)‐yl)‐N‐benzyl‐5,6,7,8‐tetrahydroquinazolin‐4‐amine ( ML241 ) specifically target the D2 domain of wild‐type p97. In addition, one of the major p97 cofactors, p47, decreases their potencies by ~50‐fold. In contrast, N2,N4‐dibenzylquinazoline‐2,4‐diamine ( DBeQ ) targets both the D1 and D2 domains and shows only a four‐ to sixfold decrease in potency against the p97–p47 complex. To elucidate structure–activity relationships for the inhibitors, we screened 200 p97 inhibitor analogues for their ability to inhibit the ATPase activity of either or both of the D1 or D2 domains, as well for their effects on p47 potency. The selectivity of 29 of these compounds was further examined by eight‐dose titrations. Four compounds showed modest selectivity for inhibiting the ATPase activity of D1. Eleven compounds inhibited D2 with greater potencies, and four showed similar potencies against D1 and D2. p47 decreased the potencies of the majority of the compounds and increased the potencies of five compounds. These results highlight the possibility of developing domain‐selective and complex‐specific p97 inhibitors in order to further elucidate the physiological roles of p97 and its cofactors. 相似文献
18.
Design,Synthesis, and Evaluation of an 18F‐Labeled Radiotracer Based on Celecoxib–NBD for Positron Emission Tomography (PET) Imaging of Cyclooxygenase‐2 (COX‐2)
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Dr. Jatinder Kaur Ole Tietz Dr. Atul Bhardwaj Alison Marshall Jenilee Way Dr. Melinda Wuest Prof. Frank Wuest 《ChemMedChem》2015,10(10):1635-1640
A series of novel fluorine‐containing cyclooxygenase‐2 (COX‐2) inhibitors was designed and synthesized based on the previously reported fluorescent COX‐2 imaging agent celecoxib–NBD ( 3 ; NBD=7‐nitrobenzofurazan). In vitro COX‐1/COX‐2 inhibitory data show that N‐(4‐fluorobenzyl)‐4‐(5‐p‐tolyl‐3‐trifluoromethylpyrazol‐1‐yl)benzenesulfonamide ( 5 ; IC50=0.36 μM , SI>277) and N‐fluoromethyl‐4‐(5‐p‐tolyl‐3‐trifluoromethylpyrazol‐1‐yl)benzenesulfonamide ( 6 ; IC50=0.24 μM , SI>416) are potent and selective COX‐2 inhibitors. Compound 5 was selected for radiolabeling with the short‐lived positron emitter fluorine‐18 (18F) and evaluated as a positron emission tomography (PET) imaging agent. Radiotracer [18F] 5 was analyzed in vitro and in vivo using human colorectal cancer model HCA‐7. Although radiotracer uptake into COX‐2‐expressing HCA‐7 cells was high, no evidence for COX‐2‐specific binding was found. Radiotracer uptake into HCA‐7 tumors in vivo was low and similar to that of muscle, used as reference tissue. 相似文献
19.
Synthesis and in vivo Evaluation of Fluorine‐18 and Iodine‐123 Pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine Derivatives as PET and SPECT Radiotracers for Mapping A2A Receptors
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Dr. Christine Vala Dr. Thomas J. Morley Dr. Xuechun Zhang Dr. Caroline Papin Dr. Adriana Alexandre S. Tavares Dr. H. Sharon Lee Dr. Cristian Constantinescu Dr. Olivier Barret Dr. Vincent M. Carroll Dr. Ronald M. Baldwin Dr. Gilles D. Tamagnan Dr. David Alagille 《ChemMedChem》2016,11(17):1936-1943
Imaging agents that target adenosine type 2A (A2A) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinson′s disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A2A‐specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [123I]MNI‐420 and [18F]MNI‐444. Herein we describe the development of both of these radiotracers by selection from a series of A2A ligands, based on the pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine core of preladenant. Each of this series of 16 ligands was found to bind to recombinant human A2A receptor in the low nanomolar range, and of these 16, six were radiolabeled with either fluorine‐18 or iodine‐123 and evaluated in nonhuman primates. These initial in vivo results resulted in the identification of 7‐(2‐(4‐(4‐(2‐[18F]fluoroethoxy)phenyl)piperazin‐1‐yl)ethyl)‐2‐(furan‐2‐yl)‐7H‐pyrazolo[4,3‐e][1,2,4]triazolo[1,5‐c]pyrimidin‐5‐amine ([18F]MNI‐444) and 7‐(2‐(4‐(2‐fluoro‐4‐[123I]iodophenyl)piperazin‐1‐yl)ethyl)‐2‐(furan‐2‐yl)‐7H‐imidazo[1,2‐c]pyrazolo[4,3‐e]pyrimidin‐5‐amine ([123I]MNI‐420) as PET and SPECT radiopharmaceuticals for mapping A2A receptors in brain. 相似文献
20.
Liping Lou Liming Jiang Jianzhao Liu Weilin Sun Zhiquan Shen 《Polymer International》2007,56(6):796-802
Two N‐phenylmaleimide derivatives bearing a chiral oxazoline group, N‐[o‐(4‐phenyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl]maleimide [(R)‐PhOPMI] and N‐[o‐(4‐isopropyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl]maleimide [(S)‐PriOPMI], were polymerized using in situ generated calixarene‐based phenates as initiators to yield optically active polymers. The formation of star‐shaped architectures was strongly dependent on both polymerization conditions and calixarene moieties. In the case of polymerization conducted in toluene at 80–100 °C, the arm‐chain numbers achieved their respective maxima for the polymers with these multifunctional initiators. In contrast, the polymers obtained in polymerizations at lower temperature possessed fewer arm chains. The structure and chiroptical properties were investigated on the basis of 13C NMR, multiangular laser light scattering, gel permeation chromatography, and circular dichroism for the macromolecules with calixarene cores. Copyright © 2006 Society of Chemical Industry 相似文献