共查询到20条相似文献,搜索用时 15 毫秒
1.
Dr. Alessandra Ammazzalorso Dr. Barbara De Filippis Dr. Letizia Giampietro Prof. Rosa Amoroso 《ChemMedChem》2013,8(10):1609-1616
Peroxisome proliferator‐activated receptors (PPARs) have been studied extensively over the last few decades and have been assessed as molecular targets for the development of drugs against metabolic disorders. A rapid increase in understanding of the physiology and pharmacology of these receptors has occurred, together with the identification of novel chemical structures that are able to activate the various PPAR subtypes. More recent evidence suggests that moderate activation of these receptors could be favorable in pathological situations due to a decrease in the side effects brought about by PPAR agonists. PPAR partial agonists and antagonists are interesting tools that are currently used to better elucidate the biological processes modulated by this family of nuclear receptors. Herein we present an overview of the various molecular structures that are able to block each of the PPAR subtypes, with a focus on promising therapeutic applications. 相似文献
2.
Design and Synthesis of Highly Active Peroxisome Proliferator‐Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity 下载免费PDF全文
Dr. Philipp M. Toth Dr. Sonja Lieber Dr. Frithjof M. Scheer Tim Schumann Dr. Yvonne Schober Dr. Wolfgang A. Nockher Dr. Till Adhikary Dr. Sabine Müller‐Brüsselbach Prof. Dr. Rolf Müller Prof. Dr. Wibke E. Diederich 《ChemMedChem》2016,11(5):488-496
Based on 3‐(((4‐(hexylamino)‐2‐methoxyphenyl)amino)sulfonyl)‐2‐thiophenecarboxylic acid methyl ester (ST247, compound 2 ), a recently described peroxisome proliferator‐activated receptor (PPAR)β/δ‐selective inverse agonist, we designed and synthesized a series of structurally related ligands. The structural modifications presented herein ultimately resulted in a series of ligands that display increased cellular activity relative to 2 . Moreover, with methyl 3‐(N‐(2‐(2‐ethoxyethoxy)‐4‐(hexylamino)phenyl)sulfamoyl)thiophene‐2‐carboxylate (PT‐S264, compound 9 u ), biologically relevant plasma concentrations in mice were achieved. The compounds presented in this study will provide useful novel tools for future investigations addressing the role of PPARβ/δ in physiological and pathophysiological processes. 相似文献
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Cover Picture: Design and Synthesis of Highly Active Peroxisome Proliferator‐Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity (ChemMedChem 5/2016) 下载免费PDF全文
Dr. Philipp M. Toth Dr. Sonja Lieber Dr. Frithjof M. Scheer Tim Schumann Dr. Yvonne Schober Dr. Wolfgang A. Nockher Dr. Till Adhikary Dr. Sabine Müller‐Brüsselbach Prof. Dr. Rolf Müller Prof. Dr. Wibke E. Diederich 《ChemMedChem》2016,11(5):445-445
4.
Dr. Laura De Lellis Prof. Annamaria Cimini Dr. Serena Veschi Dr. Elisabetta Benedetti Prof. Rosa Amoroso Prof. Alessandro Cama Dr. Alessandra Ammazzalorso 《ChemMedChem》2018,13(3):209-219
The effects on cancer‐cell proliferation and differentiation mediated by peroxisome proliferator‐activated receptors (PPARs) have been widely studied, and pleiotropic outcomes in different cancer models and under different experimental conditions have been obtained. Interestingly, few studies report and little preclinical evidence supports the potential antitumor activity of PPAR antagonists. This review focuses on recent findings on the antitumor in vitro and in vivo effects observed for compounds able to inhibit the three PPAR subtypes in different tumor models, providing a rationale for the use of PPAR antagonists in the treatment of tumors expressing the corresponding receptors. 相似文献
5.
Frédéric Denonne Dr. Franck Atienzar Dr. Sylvain Célanire Dr. Bernard Christophe Dr. Frédérique Delannois Dr. Christel Delaunoy Marie‐Laure Delporte Dr. Véronique Durieu Michel Gillard Dr. Bénédicte Lallemand Yves Lamberty Dr. Geneviève Lorent Dr. Alain Vanbellinghen Nathalie Van houtvin Valérie Verbois Laurent Provins Dr. 《ChemMedChem》2010,5(2):206-212
6.
Pharmacophore‐Based Design of Novel Oxadiazoles as Selective Sphingosine‐1‐phosphate (S1P) Receptor Agonists with in vivo Efficacy 下载免费PDF全文
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
7.
Evaluation of (4‐Arylpiperidin‐1‐yl)cyclopentanecarboxamides As High‐Affinity and Long‐Residence‐Time Antagonists for the CCR2 Receptor 下载免费PDF全文
Dr. Maris Vilums Dr. Annelien J. M. Zweemer Arian Dilanchian Jacobus P. D. van Veldhoven Henk de Vries Dr. Johannes Brussee Dr. John Saunders Dr. Dean Stamos Dr. Laura H. Heitman Prof. Adriaan P. IJzerman 《ChemMedChem》2015,10(7):1249-1258
Animal models suggest that the chemokine ligand 2/CC‐chemokine receptor 2 (CCL2/CCR2) axis plays an important role in the development of inflammatory diseases. However, CCR2 antagonists have failed in clinical trials because of a lack of efficacy. We previously described a new approach for the design of CCR2 antagonists by the use of structure–kinetics relationships (SKRs). Herein we report new findings on the structure–affinity relationships (SARs) and SKRs of the reference compound MK‐0483, its diastereomers, and its structural analogues as CCR2 antagonists. The SARs of the 4‐arylpiperidine group suggest that lipophilic hydrogen‐bond‐accepting substituents at the 3‐position are favorable. However, the SKRs suggest that a lipophilic group with a certain size is desired [e.g., 3‐Br: Ki=2.8 nM , residence time (tres)=243 min; 3‐iPr: Ki=3.6 nM , tres=266 min]. Alternatively, additional substituents and further optimization of the molecule, while keeping a carboxylic acid at the 3‐position, can also prolong tres; this was most prominently observed in MK‐0483 (Ki=1.2 nM , tres=724 min) and a close analogue (Ki=7.8 nM ) with a short residence time. 相似文献
8.
Anja Kraus Dr. Prasanta Ghorai Dr. Tobias Birnkammer David Schnell Sigurd Elz Prof. Dr. Roland Seifert Prof. Dr. Stefan Dove Prof. Dr. Günther Bernhardt Prof. Dr. Armin Buschauer Prof. Dr. 《ChemMedChem》2009,4(2):232-240
Bioisosteric replacement of the guanidino group in arpromidine‐like histamine H2 receptor (H2R) agonists by an acylguanidine moiety is useful for obtaining potent H2R agonists with improved oral bioavailability and blood–brain barrier penetration. We show that bioisosteric replacement of the imidazole ring in NG‐acylated imidazolylpropylguanidines by a 2‐aminothiazol‐5‐yl group resulted in potent H2R agonists with much greater selectivity for the human H2R over H3 and H4 receptors.
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Sylvain Célanire Dr. Maikel Wijtmans Dr. Bernard Christophe Dr. Philippe Collart Iwan de Esch Dr. Donald Dassesse Dr. Christel Delaunoy Frédéric Denonne Dr. Véronique Durieu Edith Gelens Dr. Michel Gillard Dr. Bénédicte Lallemand Yves Lamberty Dr. Florence Lebon Dr. Jean‐Marie Nicolas Dr. Luc Quéré Dr. Erwin Snip Dr. Alain Vanbellinghen Nathalie Van houtvin Valérie Verbois Henk Timmerman Prof. Dr. Patrice Talaga Dr. Rob Leurs Prof. Dr. Laurent Provins Dr. 《ChemMedChem》2009,4(7):1063-1068
H 3 R inverse agonists based on an aminopropoxy‐phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.
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Dr. Teemu Haikarainen Dr. Jarkko Koivunen Mohit Narwal Harikanth Venkannagari Ezeogo Obaji Päivi Joensuu Prof. Taina Pihlajaniemi Dr. Lari Lehtiö 《ChemMedChem》2013,8(12):1978-1985
Human tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a set of highly potent tankyrase inhibitors based on a 2‐phenyl‐3,4‐dihydroquinazolin‐4‐one scaffold. Substitutions at the para position of the scaffold′s phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single‐digit nanomolar potencies, and profiling against several human diphtheria‐toxin‐like ADP‐ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X‐ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2‐phenyl‐3,4‐dihydroquinazolin‐4‐one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain. 相似文献
11.
Targeting an Aromatic Hotspot in Plasmodium falciparum 1‐Deoxy‐d‐xylulose‐5‐phosphate Reductoisomerase with β‐Arylpropyl Analogues of Fosmidomycin 下载免费PDF全文
Dr. Sanjeewani Sooriyaarachchi René Chofor Martijn D. P. Risseeuw Terese Bergfors Dr. Jenny Pouyez Dr. Cynthia S. Dowd Dr. Louis Maes Dr. Johan Wouters Dr. T. Alwyn Jones Dr. Serge Van Calenbergh Dr. Sherry L. Mowbray 《ChemMedChem》2016,11(18):2024-2036
Blocking the 2‐C‐methyl‐d ‐erythrithol‐4‐phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3‐(N‐hydroxyformamido)propyl)phosphonic acid, 1 ] and its acetyl homologue FR‐900098 [(3‐(N‐hydroxyacetamido)propyl)phosphonic acid, 2 ] potently inhibit 1‐deoxy‐d ‐xylulose‐5‐phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β‐position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2 . Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X‐ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active‐site flap, which had made favorable interactions with 1 and 2 . Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta‐substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency. 相似文献
12.
Progress in understanding peroxisome proliferator-activated receptor (PPAR) subtypes as nuclear receptors that have pleiotropic effects on biological responses has enabled the exploration of new subtype-selective PPAR ligands. Such ligands are useful chemical biology/pharmacological tools to investigate the functions of PPARs and are also candidate drugs for the treatment of PPAR-mediated diseases, such as metabolic syndrome, inflammation and cancer. This review summarizes our medicinal chemistry research of more than 20 years on the design, synthesis, and pharmacological evaluation of subtype-selective PPAR agonists, which has been based on two working hypotheses, the ligand superfamily concept and the helix 12 (H12) holding induction concept. X-ray crystallographic analyses of our agonists complexed with each PPAR subtype validate our working hypotheses. 相似文献
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Matthias Goebel Markus Clemenz Bart Staels Prof. Dr. Thomas Unger Prof. Dr. Ulrich Kintscher Prof. Dr. Ronald Gust Prof. Dr. 《ChemMedChem》2009,4(3):445-456
Telmisartan was originally designed as an AT1 antagonist but was later also characterized as a selective PPARγ modulator. This study focused on the identification of the essential structural motifs of telmisartan for PPARγ activation activity, elucidating the individual SAR of each different component (shown).
15.
Mark J. Thompson Dr. Jennifer C. Louth Gemma K. Greenwood Dr. Fiona J. Sorrell Sandra G. Knight Nathan B. P. Adams Beining Chen Dr. 《ChemMedChem》2010,5(9):1476-1488
Amide derivatives of 2,4‐diarylthiazole‐5‐carboxylic acids were synthesised and tested for efficacy in a cell line model of prion disease. A number of compounds demonstrating antiprion activity were thereby identified from the screening libraries, showing improved potency and reproducibility of results relative to amide derivatives of the related 2,4‐diphenyl‐5‐aminothiazole, which have been documented previously. Thus, 'switching' the sense of the amide bond at thiazole C5 revealed a more promising lead series of potential prion disease therapeutics. Furthermore, 3,5‐diaryl‐1,2,4‐thiadiazoles isolated as by‐products during library synthesis provided a handful of additional examples possessing an antiprion effect, thereby augmenting the set of newly identified active compounds. Evaluation of binding to cellular prion protein (PrPC) showed only weak affinities at best, suggesting that the newly identified antiprion agents do not mediate their biological effect through direct interaction with PrPC. 相似文献
16.
Dr. Lena Herbst Dr. Matthias Goebel Sebastian Bandholtz Prof. Dr. Ronald Gust Prof. Dr. Ulrich Kintscher 《ChemMedChem》2012,7(11):1935-1942
Selective modulation of the peroxisome proliferator‐activated receptor gamma (PPARγ) by direct binding of small molecules demonstrates a promising tool for treatment of insulin resistance and type 2 diabetes mellitus. Besides its blood pressure‐lowering properties, the AT1‐receptor blocker telmisartan has been shown to be a partial agonist of PPARγ with beneficial metabolic effects in vitro and in mice. In our previous work, comprehensive structure–activity relationship (SAR) studies discussed the different parts of the telmisartan structure and various moieties. Based on these findings, we designed and synthesized new PPARγ ligands with a benzimidazole (agonists 4 ‐ 5 and 4 ‐ 6 ), benzothiophene (agonists 5 ‐ 5 and 5 ‐ 6 ) or benzofuran (agonists 6 ‐ 5 and 6 ‐ 6 ) moiety either at position 5 or 6 of the benzimidazole core structure. Lipophilicity and EC50 values were improved for all new compounds compared with telmisartan. Regarding PPARγ activation, the compounds were characterized by a differentiation assay using 3T3‐L1 cells and a luciferase assay with COS‐7 cells transiently transfected with pGal4‐hPPARgDEF, pGal5‐TK‐pGL3 and pRL‐CMV. A decrease in both potency and efficacy was observed after the shift of either the benzothiophene or the benzofuran moiety from position 6 to position 5. Selective recruitment of the coactivators TRAP220, SRC‐1 and PGC‐1α, and release of corepressor NCoR1 determined by time‐resolved fluorescence resonance energy transfer (TR‐FRET) was detected depending on residues in position 5 or 6. 相似文献
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Kimberly M. Bonger Dr. Richard J. B. H. N. van den Berg Dr. Annemiek D. Knijnenburg Laura H. Heitman Dr. Chris J. van Koppen Dr. Cornelis M. Timmers Dr. Herman S. Overkleeft Prof. Dr. Gijsbert A. van der Marel Prof. Dr. 《ChemMedChem》2009,4(7):1189-1195
Two series of dimeric ligands for a G‐protein‐coupled receptor were prepared that differ by the interconnecting spacer system. Biological evaluation revealed that both dimeric series exhibit unique biological properties relative to their monomeric counterparts.
19.
Florian Witzgall Tobias Depke Dr. Michael Hoffmann Dr. Martin Empting Prof. Dr. Mark Brönstrup Prof. Dr. Rolf Müller Prof. Dr. Wulf Blankenfeldt 《Chembiochem : a European journal of chemical biology》2018,19(14):1531-1544
Pseudomonas aeruginosa is a bacterial pathogen that causes life‐threatening infections in immunocompromised patients. It produces a large armory of saturated and mono‐unsaturated 2‐alkyl‐4(1H)‐quinolones (AQs) and AQ N‐oxides (AQNOs) that serve as signaling molecules to control the production of virulence factors and that are involved in membrane vesicle formation and iron chelation; furthermore, they also have, for example, antibiotic properties. It has been shown that the β‐ketoacyl‐acyl‐carrier protein synthase III (FabH)‐like heterodimeric enzyme PqsBC catalyzes the last step in the biosynthesis of the most abundant AQ congener, 2‐heptyl‐4(1H)‐quinolone (HHQ), by condensing octanoyl‐coenzyme A (CoA) with 2‐aminobenzoylacetate (2‐ABA), but the basis for the large number of other AQs/AQNOs produced by P. aeruginosa is not known. Here, we demonstrate that PqsBC uses different medium‐chain acyl‐CoAs to produce various saturated AQs/AQNOs and that it also biosynthesizes mono‐unsaturated congeners. Further, we determined the structures of PqsBC in four different crystal forms at 1.5 to 2.7 Å resolution. Together with a previous report, the data reveal that PqsBC adopts open, intermediate, and closed conformations that alter the shape of the acyl‐binding cavity and explain the promiscuity of PqsBC. The different conformations also allow us to propose a model for structural transitions that accompany the catalytic cycle of PqsBC that might have broader implications for other FabH‐enzymes, for which such structural transitions have been postulated but have never been observed. 相似文献
20.
Prashant S. Kharkar Dr. Angela M. Batman Juan Zhen Dr. Patrick M. Beardsley Prof. Maarten E. A. Reith Prof. Aloke K. Dutta Prof. 《ChemMedChem》2009,4(7):1075-1085
A novel series of optically active molecules based on a 4‐(2‐(benzhydryloxy)ethyl)‐1‐((R)‐2‐hydroxy‐2‐phenylethyl)‐piperidin‐3‐ol template were developed. Depending on stereochemistry, the compounds exhibit various degrees of affinity for three dopamine, serotonin, and norepinephrine transporters. These molecules have the potential for treating several neurological disorders such as drug abuse, depression, and attention deficit hyperactivity disorder.