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1.
Discovery of α‐Substituted Imidazole‐4‐acetic Acid Analogues as a Novel Class of ρ1 γ‐Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone 下载免费PDF全文
Dr. Jacob Krall Benjamin M. Brygger Sara B. Sigurðardóttir Dr. Clarissa K. L. Ng Dr. Christoffer Bundgaard Dr. Jan Kehler Birgitte Nielsen Prof. Toke Bek Prof. Anders A. Jensen Prof. Bente Frølund 《ChemMedChem》2016,11(20):2299-2310
The ρ‐containing γ‐aminobutyric acid type A receptors (GABAARs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABAARs are of interest. In this study, we demonstrate that the partial GABAAR agonist imidazole‐4‐acetic acid (IAA) is able to penetrate the blood–brain barrier in vivo; we prepared a series of α‐ and N‐alkylated, as well as bicyclic analogues of IAA to explore the structure–activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l ‐histidine by an efficient minimal‐step synthesis, and their pharmacological properties were characterized at native rat GABAARs in a [3H]muscimol binding assay and at recombinant human α1β2γ2S and ρ1 GABAARs using the FLIPR? membrane potential assay. The (+)‐α‐methyl‐ and α‐cyclopropyl‐substituted IAA analogues ((+)‐ 6 a and 6 c , respectively) were identified as fairly potent antagonists of the ρ1 GABAAR that also displayed significant selectivity for this receptor over the α1β2γ2S GABAAR. Both 6 a and 6 c were shown to inhibit GABA‐induced relaxation of retinal arterioles from porcine eyes. 相似文献
2.
Novel Hinge‐Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure–Activity Relationship Study on Tofacitinib Bioisosteres 下载免费PDF全文
Matthias Gehringer Michael Forster Ellen Pfaffenrot Silke M. Bauer Prof. Dr. Stefan A. Laufer 《ChemMedChem》2014,9(11):2516-2527
The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H‐pyrrolo[2,3‐d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure–activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models. 相似文献
3.
Jun Young Kim Ji Won Lee Young Soo Kim Yuno Lee Dr. Young Bae Ryu Songmi Kim Hyung Won Ryu Marcus J. Curtis‐Long Prof. Dr. Keun Woo Lee Dr. Woo Song Lee Prof. Dr. Ki Hun Park 《Chembiochem : a European journal of chemical biology》2010,11(15):2125-2131
Competitive glycosidase inhibitors are generally sugar mimics that are costly and tedious to obtain because they require challenging and elongated chemical synthesis, which must be stereo‐ and regiocontrolled. Here, we show that readily accessible achiral (E)‐1‐phenyl‐3‐(4‐strylphenyl)ureas are potent competitive α‐glucosidase inhibitors. A systematic synthesis study shows that the 1‐phenyl moiety on the urea is critical for ensuring competitive inhibition, and substituents on both terminal phenyl groups contribute to inhibition potency. The most potent inhibitor, compound 12 (IC50=8.4 μM , Ki=3.2 μM ), manifested a simple slow‐binding inhibition profile for α‐glucosidase with the kinetic parameters k3=0.005256 μM ?1 min?1, k4=0.003024 min?1, and ${K{{{\rm app}\hfill \atop {\rm i}\hfill}}}$ =0.5753 μM . 相似文献
4.
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
5.
Jeeyeon Kim Youngjae Kim Prof. Jinsung Tae Miyoung Yeom Prof. Bongjin Moon Dr. Xi‐Ping Huang Prof. Bryan L. Roth Kangho Lee Dr. Hyewhon Rhim Prof. Il Han Choo Prof. Youhoon Chong Dr. Gyochang Keum Dr. Ghilsoo Nam Prof. Hyunah Choo 《ChemMedChem》2013,8(11):1855-1864
The 5‐HT7 receptor (5‐HT7R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5‐HT7R antagonist SB‐269970 exhibited antidepressant‐like activity, whereas systemic administration of the 5‐HT7R agonist AS‐19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5‐HT7R antagonists or agonists, aryl biphenyl‐3‐ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5‐HT7R. Among the synthesized compounds, 1‐([2′‐methoxy‐(1,1′‐biphenyl)‐3‐yl]methyl)‐4‐(2‐methoxyphenyl)piperazine ( 28 ) was the best binder to the 5‐HT7R (pKi=7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5‐HT7R over other serotonin receptor subtypes, such as 5‐HT1R, 5‐HT2R, 5‐HT3R, and 5‐HT6R. In a molecular modeling study, the 2‐methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function. 相似文献
6.
Silvia Franchini Dr. Annalisa Tait Prof. Adolfo Prandi Dr. Claudia Sorbi Dr. Rossella Gallesi Michela Buccioni Dr. Gabriella Marucci Prof. Carla De Stefani Dr. Antonio Cilia Dr. Livio Brasili Prof. 《ChemMedChem》2009,4(2):196-203
A selective 5‐HT 1A receptor agonist : A new series of ligands acting at 5‐HT1A serotonin receptor were identified. Among them (2,2‐diphenyl‐[1,3]oxathiolan‐5‐yl‐methyl)‐(3‐phenyl‐propyl)amine (shown) possesses outstanding activity (pKi=8.72, pD2=7.67, Emax=85) and selectivity (5‐HT1A/α1D>150), and represents a new 5‐HT1A agonist chemotype.
7.
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.
8.
David B. Whitman Christopher D. Cox Dr. Michael J. Breslin Karen M. Brashear John D. Schreier Michael J. Bogusky Dr. Rodney A. Bednar Dr. Wei Lemaire Joseph G. Bruno George D. Hartman Dr. Duane R. Reiss C. Meacham Harrell Richard L. Kraus Dr. Yuxing Li Susan L. Garson Scott M. Doran Dr. Thomayant Prueksaritanont Dr. Chunze Li Dr. Christopher J. Winrow Dr. Kenneth S. Koblan Dr. John J. Renger Paul J. Coleman Dr. 《ChemMedChem》2009,4(7):1069-1074
Silent Night : Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX1R/OX2R) orexin receptor antagonist featuring a 1,4‐diazepane central constraint that blocks orexin signaling in vivo. In telemetry‐implanted rats, oral administration of this antagonist produced a decrease in wakefulness, while increasing REM and non‐REM sleep.
9.
Gheorghe Roman Dr. Jason Z. Vlahakis Dr. Dragic Vukomanovic Dr. Kanji Nakatsu Prof. Walter A. Szarek Prof. 《ChemMedChem》2010,5(9):1541-1555
Previous studies by our research group have been concerned with the design of selective inhibitors of heme oxygenases (HO‐1 and HO‐2). The majority of these were based on a four‐carbon linkage of an azole, usually an imidazole, and an aromatic moiety. In the present study, we designed and synthesized a series of inhibition candidates containing a shorter linkage between these groups, specifically, a series of 1‐aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and their derivatives. As regards HO‐1 inhibition, the aromatic moieties yielding best results were found to be halogen‐substituted residues such as 3‐bromophenyl, 4‐bromophenyl, and 3,4‐dichlorophenyl, or hydrocarbon residues such as 2‐naphthyl, 4‐biphenyl, 4‐benzylphenyl, and 4‐(2‐phenethyl)phenyl. Among the imidazole‐ketones, five ( 36 – 39 , and 44 ) were found to be very potent (IC50<5 μM ) toward both isozymes. Relative to the imidazole‐ketones, the series of corresponding triazole‐ketones showed four compounds ( 54 , 55 , 61 , and 62 ) having a selectivity index >50 in favor of HO‐1. In the case of the azole‐dioxolanes, two of them ( 80 and 85 ), each possessing a 2‐naphthyl moiety, were found to be particularly potent and selective HO‐1 inhibitors. Three non‐carbonyl analogues ( 87 , 89 , and 91 ) of 1‐(4‐chlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethanone were found to be good inhibitors of HO‐1. For the first time in our studies, two azole‐based inhibitors ( 37 and 39 ) were found to exhibit a modest selectivity index in favor of HO‐2. The present study has revealed additional candidates based on inhibition of heme oxygenases for potentially useful pharmacological and therapeutic applications. 相似文献
10.
Synthesis,Structure–Activity,and Structure–Stability Relationships of 2‐Substituted‐N‐(4‐oxo‐3‐oxetanyl) N‐Acylethanolamine Acid Amidase (NAAA) Inhibitors 下载免费PDF全文
Romina Vitale Dr. Giuliana Ottonello Rita Petracca Sine Mandrup Bertozzi Dr. Stefano Ponzano Dr. Andrea Armirotti Dr. Anna Berteotti Dr. Mauro Dionisi Prof. Andrea Cavalli Prof. Daniele Piomelli Dr. Tiziano Bandiera Dr. Fabio Bertozzi 《ChemMedChem》2014,9(2):323-336
N‐Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator‐activated receptor‐α (PPAR‐α). Compounds that feature an α‐amino‐β‐lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti‐inflammatory effects that are mediated through FAE‐dependent activation of PPAR‐α. We synthesized and tested a series of racemic, diastereomerically pure β‐substituted α‐amino‐β‐lactones, as either carbamate or amide derivatives, investigating the structure–activity and structure–stability relationships (SAR and SSR) following changes in β‐substituent size, relative stereochemistry at the α‐ and β‐positions, and α‐amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the β‐position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability. 相似文献
11.
Synthesis,Structure–Activity Relationship Studies,and ADMET Properties of 3‐Aminocyclohex‐2‐en‐1‐ones as Chemokine Receptor 2 (CXCR2) Antagonists 下载免费PDF全文
Weiyang Dai Dr. Wenmin Chen Dr. Bikash Debnath Prof. Yong Wu Prof. Nouri Neamati 《ChemMedChem》2018,13(9):916-930
Herein we describe the synthesis and structure–activity relationships of 3‐aminocyclohex‐2‐en‐1‐one derivatives as novel chemokine receptor 2 (CXCR2) antagonists. Thirteen out of 44 derivatives were found to inhibit CXCR2 downstream signaling in a Tango assay specific for CXCR2, with IC50 values less than 10 μm . In silico ADMET prediction suggests that all active compounds possess drug‐like properties. None of these compounds show significant cytotoxicity, suggesting their potential application in inflammatory mediated diseases. A structure–activity relationship (SAR) map has been generated to gain better understanding of their binding mechanism to guide further optimization of these new CXCR2 antagonists. 相似文献
12.
Antonio Peón Dr. Claire Coderch Prof. Federico Gago Prof. Concepción González‐Bello 《ChemMedChem》2013,8(5):740-747
Herein we report comparative binding energy (COMBINE) analyses to derive quantitative structure–activity relationship (QSAR) models that help rationalize the determinants of binding affinity for inhibitors of type II dehydroquinase (DHQ2), the third enzyme of the shikimic acid pathway. Independent COMBINE models were derived for Helicobacter pylori and Mycobacterium tuberculosis DHQ2, which is an essential enzyme in both these pathogenic bacteria that has no counterpart in human cells. These studies quantify the importance of the hydrogen bonding interactions between the ligands and the water molecule involved in the DHQ2 reaction mechanism. They also highlight important differences in the ligand interactions with the interface pocket close to the active site that could provide guides for future inhibitor design. 相似文献
13.
1‐(1H‐Indol‐3‐yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors 下载免费PDF全文
Dr. Arnaud Hequet Dr. Olga N. Burchak Dr. Matthieu Jeanty Dr. Xavier Guinchard Dr. Emmanuelle Le Pihive Dr. Laure Maigre Pascale Bouhours Prof. Dominique Schneider Prof. Max Maurin Dr. Jean‐Marc Paris Dr. Jean‐Noël Denis Prof. Dr. Claude Jolivalt 《ChemMedChem》2014,9(7):1534-1545
The synthesis of 37 1‐(1H‐indol‐3‐yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti‐staphylococcal activity. By contrast, several of the compounds restored, in a concentration‐dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure–activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)‐N‐benzylidene‐2‐(tert‐butoxycarbonylamino)‐1‐(5‐iodo‐1H‐indol‐3‐yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA‐1199B strain when used at a concentration of 0.5 mg L ?1. To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert‐butyl (2‐(3‐hydroxyureido)‐2‐(1H‐indol‐3‐yl)ethyl)carbamate, which is not toxic for human cells, was also found. 相似文献
14.
Synthesis, σ Receptor Affinity,and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines 下载免费PDF全文
Dr. Peer Hasebein Bastian Frehland Dr. Dirk Schepmann Prof. Dr. Bernhard Wünsch 《ChemMedChem》2014,9(8):1697-1703
In accordance with a novel strategy for generating the 2‐benzazepine scaffold by connecting C6–C1 and C3–N building blocks, a set of 5‐phenylsulfanyl‐ and 5‐benzyl‐substituted tetrahydro‐2‐benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ1 affinity was achieved for 2‐benzazepines with linear or branched alk(en)yl residues containing at least an n‐butyl substructure. The butyl‐ and 4‐fluorobenzyl‐substituted derivatives, (±)‐5‐benzyl‐2‐butyl‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine ( 19 b ) and (±)‐5‐benzyl‐2‐(4‐fluorobenzyl)‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine ( 19 m ), show high selectivity over more than 50 other relevant targets, including the σ2 subtype and various binding sites of the N‐methyl‐D ‐aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition‐enhancing activity. Compound 19 m did not have any antidepressant‐like effects in mice. 相似文献
15.
Bastian Tewes Dr. Bastian Frehland Dirk Schepmann Dr. Kai‐Uwe Schmidtke Thomas Winckler Prof. Dr. Bernhard Wünsch Prof. Dr. 《ChemMedChem》2010,5(5):687-695
Cleavage and reconstitution of a bond in the piperidine ring of ifenprodil ( 1 ) leads to 7‐methoxy‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ols, a novel class of NR2B‐selective NMDA receptor antagonists. The secondary amine 7‐methoxy‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ol ( 12 ), which was synthesized in six steps starting from 2‐phenylethylamine 3 , represents the central building block for the introduction of several N‐linked residues. A distance of four methylene units between the basic nitrogen atom and the phenyl residue in the side chain results in high NR2B affinity. The 4‐phenylbutyl derivative 13 (WMS‐1405, Ki=5.4 nM ) and the conformationally restricted 4‐phenylcyclohexyl derivative 31 (Ki=10 nM ) represent the most potent NR2B ligands of this series. Whereas 13 shows excellent selectivity, the 4‐phenylcyclohexyl derivative 31 also interacts with σ1 (Ki=33 nM ) and σ2 receptors (Ki=82 nM ). In the excitotoxicity assay the phenylbutyl derivative 13 inhibits the glutamate‐induced cytotoxicity with an IC50 value of 360 nM , indicating that 13 is an NMDA antagonist. 相似文献
16.
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
17.
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
18.
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
19.
Synthesis and Pharmacological Evaluation of α4β2 Nicotinic Ligands with a 3‐Fluoropyrrolidine Nucleus 下载免费PDF全文
Dr. Lucia Tamborini Dr. Andrea Pinto Dr. Roberta Ettari Dr. Cecilia Gotti Dr. Francesca Fasoli Prof. Paola Conti Prof. Carlo De Micheli 《ChemMedChem》2015,10(6):1071-1078
Nicotinic acetylcholine receptors (nAChRs) play an important role in many central nervous system disorders such as Alzheimer’s and Parkinson’s diseases, schizophrenia, and mood disorders. The α4β2 subtype has emerged as an important target for the early diagnosis and amelioration of Alzheimer’s disease symptoms. Herein we report a new class of α4β2 receptor ligands characterized by a basic pyrrolidine nucleus, the basicity of which was properly decreased through the insertion of a fluorine atom at the 3‐position, and a pyridine ring carrying at the 3‐position substituents known to positively affect affinity and selectivity toward the α4β2 subtype. Derivatives 3‐(((2S,4R)‐4‐fluoropyrrolidin‐2‐yl)methoxy)‐5‐(phenylethynyl)pyridine ( 11 ) and 3‐((4‐fluorophenyl)ethynyl)‐5‐(((2S,4R)‐4‐fluoropyrrolidin‐2‐yl)methoxy)pyridine ( 12 ) were found to be the most promising ligands identified in this study, showing good affinity and selectivity for the α4β2 subtype and physicochemical properties predictive of a relevant central nervous system penetration. 相似文献
20.
Matthias Goebel Dr. Bart Staels Prof. Dr. Thomas Unger Prof. Dr. Ulrich Kintscher Prof. Dr. Ronald Gust Prof. Dr. 《ChemMedChem》2009,4(7):1136-1142
Probing SAR : The 1‐(biphenyl‐4‐ylmethyl)‐1H‐benzo[d]imidazole moiety is known to be an essential structural component of telmisartan for PPARγ activation. This study focused on the substituents at position 2 of the benzimidazole in an attempt to optimize PPARγ activation. In particular, the elongation of the alkyl chain and the introduction of an aromatic ring system were studied (shown).