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1.
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
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Claudia Sorbi Dr. Silvia Franchini Dr. Annalisa Tait Prof. Adolfo Prandi Dr. Rossella Gallesi Piero Angeli Prof. Gabriella Marucci Prof. Lorenza Pirona Dr. Elena Poggesi Dr. Livio Brasili Prof. 《ChemMedChem》2009,4(3):393-399
Conformational restriction of naftopidil led to the discovery of a new class of ligands with a 1,3‐dioxolane (1,3‐oxathiolane, 1,3‐dithiolane) structure that bind to α1 adrenoceptor subtypes and 5‐HT1A receptors. Adequate structural modifications address the selectivity toward one or the other receptor system.
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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
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Targeting Serotonin 2A and Adrenergic α1 Receptors for Ocular Antihypertensive Agents: Discovery of 3,4‐Dihydropyrazino[1,2‐b]indazol‐1(2H)‐one Derivatives 下载免费PDF全文
Dr. Guido Furlotti Dr. Maria Alessandra Alisi Dr. Nicola Cazzolla Dr. Francesca Ceccacci Dr. Beatrice Garrone Dr. Tecla Gasperi Dr. Angela La Bella Prof. Dr. Francesca Leonelli Prof. Dr. Maria Antonietta Loreto Dr. Gabriele Magarò Giorgina Mangano Prof. Dr. Rinaldo Marini Bettolo Dr. Emanuela Masini Dr. Martina Miceli Dr. Luisa Maria Migneco Dr. Marco Vitiello 《ChemMedChem》2018,13(15):1597-1607
Glaucoma affects millions of people worldwide and causes optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and decreasing IOP is the key therapeutic target of current pharmacological treatments. As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic α1) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic N2‐alkyl‐indazole‐amide derivatives. This study identified a 3,4‐dihydropyrazino[1,2‐b]indazol‐1(2H)‐one derivative with potent serotonin 2A receptor antagonism, >100‐fold selectivity over other serotonin subtype receptors, and high affinity for the α1 receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action in vivo relative to the clinically used reference compound timolol. 相似文献
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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
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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.
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The role of β‐aminovinyl ketones as synthetic intermediates has been well categorised, but recent developments have shown an interesting array of applications and new chemotherapeutic potential, both in the preparation of biologically active heterocycles and as pharmacophores in their own right.
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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
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Gaetano Giammona Gennara Cavallaro Giovanna Pitarresi Elisa Pedone 《Polymer International》2000,49(1):93-98
In the present study the derivatization of two water‐soluble synthetic polymers, α,β‐poly(N‐2‐hydroxyethyl)‐DL ‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy), with glycidyltrimethylammonium chloride (GTA) is described. This reaction permits the introduction of positive charges in the macromolecular chains of PHEA and PAHy in order to make easier the electrostatic interaction with DNA. Different parameters affect the reaction of derivatization, such as GTA concentration and reaction time. PHEA reacts partially and slowly with GTA; on the contrary the reaction of PAHy with GTA is more rapid and extensive. The derivatization of PHEA and PAHy with GTA is a convenient method to introduce positive groups in their chains and it permits the preparation of interpolyelectrolyte complexes with DNA. © 2000 Society of Chemical Industry 相似文献
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Krishna Bahadur SomaiMagar Yong Rok Lee 《Advanced Synthesis \u0026amp; Catalysis》2014,356(16):3422-3432
Efficient one‐step syntheses of α,β‐ and β,β‐dihaloenones were achieved by ruthenium(II)‐catalyzed reactions between cyclic or acyclic diazodicarbonyl compounds and oxalyl chloride or oxalyl bromide in moderate to good yields. This methodology offers several significant advantages, which include ease of handling, mild reaction conditions, one‐step reaction, and the use of an effective and non‐toxic catalyst. The synthesized compounds were further transformed into highly functionalized novel molecules bearing aromatic rings on the enone moiety using the Suzuki reaction.
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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
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Modification of isotactic polypropylene (iPP) with two nucleation agents, namely 1,3:24‐bis(3,4‐dimethylobenzylideno) sorbitol (DMDBS) (α‐nucleator) and N, N′‐dicyclohexylo‐2,6‐naphthaleno dicarboxy amide (NJ) (β‐nucleator), leads to significant changes of the structure, morphology and properties. Both nucleating agents cause an increase in the crystallization temperature. The efficiency determined in a self‐nucleation test is 73.4 % for DMDBS and 55.9 % for NJ. The modification with NJ induces the creation of the hexagonal β‐form of iPP. The addition of DMDBS lowers the haze of iPP while the presence of NJ increases the haze. Copyright © 2004 Society of Chemical Industry 相似文献
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5‐(Piperidin‐4‐yl)‐3‐Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ‐Aminobutyric Acid Type A Receptor Binding Site 下载免费PDF全文
Dr. Jacob Krall Dr. Kenneth T. Kongstad Birgitte Nielsen Troels E. Sørensen Dr. Thomas Balle Dr. Anders A. Jensen Dr. Bente Frølund 《ChemMedChem》2014,9(11):2475-2485
A series of bioisosteric N1‐ and N2‐substituted 5‐(piperidin‐4‐yl)‐3‐hydroxypyrazole analogues of the partial GABAAR agonists 4‐PIOL and 4‐PHP have been designed, synthesized, and characterized pharmacologically. The unsubstituted 3‐hydroxypyrazole analogue of 4‐PIOL ( 2 a ; IC50~300 μM ) is a weak antagonist at the α1β2γ2 GABAAR, whereas substituting the N1‐ or N2‐position with alkyl or aryl substituents resulted in antagonists with binding affinities in the high nanomolar to low micromolar range at native rat GABAARs. Docking studies using a α1β2γ2 GABAAR homology model along with the obtained SAR indicate that the N1‐substituted analogues of 4‐PIOL and 4‐PHP, 2 a – k , and previously reported 3‐substituted 4‐PHP analogues share a common binding mode to the orthosteric binding site in the receptor. Interestingly, the core scaffold of the N2‐substituted analogues of 4‐PIOL and 4‐PHP, 3 b – k , are suggested to flip 180° thereby adapting to the binding pocket and addressing a cavity situated above the core scaffold. 相似文献
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Paola Matarrese Sonia Maccari Barbara Ascione Rosa Vona Vanessa Vezzi Tonino Stati Maria Cristina Gr Giuseppe Marano Caterina Ambrosio Paola Molinari 《International journal of molecular sciences》2022,23(9)
Adrenergic receptors (AR) belong to the G protein-coupled receptor superfamily and regulate migration and proliferation in various cell types. The objective of this study was to evaluate whether β-AR stimulation affects the antiproliferative action of α2-AR agonists on B16F10 cells and, if so, to determine the relative contribution of β-AR subtypes. Using pharmacological approaches, evaluation of Ki-67 expression by flow cytometry and luciferase-based cAMP assay, we found that treatment with isoproterenol, a β-AR agonist, increased cAMP levels in B16F10 melanoma cells without affecting cell proliferation. Propranolol inhibited the cAMP response to isoproterenol. In addition, stimulation of α2-ARs with agonists such as clonidine, a well-known antihypertensive drug, decreased cancer cell proliferation. This effect on cell proliferation was suppressed by treatment with isoproterenol. In turn, the suppressive effects of isoproterenol were abolished by the treatment with either ICI 118,551, a β2-AR antagonist, or propranolol, suggesting that isoproterenol effects are mainly mediated by the β2-AR stimulation. We conclude that the crosstalk between the β2-AR and α2-AR signaling pathways regulates the proliferative activity of B16F10 cells and may therefore represent a therapeutic target for melanoma therapy. 相似文献
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Ligand‐Free Nickel‐Catalysed 1,4‐Addition of Arylboronic Acids to α,β‐Unsaturated Carbonyl Compounds
Wen Chen Lu Sun Xi Huang Jiayi Wang Yanqing Peng Gonghua Song 《Advanced Synthesis \u0026amp; Catalysis》2015,357(7):1474-1482
A simple and efficient ligand‐free nickel‐based catalytic system has been developed for the 1,4‐addition of arylboronic acids to α,β‐unsaturated carbonyl compounds. With catalyst loadings of 1–2 mol%, a series of 1,4‐adducts from chalcones and cinnamates was obtained in moderate to excellent yields within 5–30 min under a nitrogen atmosphere and microwave irradiation. The 1,4‐addition of arylboronic acids to acrylates is less efficient.
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Yohan Park Young Ju Lee Suckchang Hong Mi‐hyun Kim Myungmo Lee Taek‐Soo Kim Jae Kyun Lee Sang‐sup Jew Hyeung‐geun Park 《Advanced Synthesis \u0026amp; Catalysis》2011,353(18):3313-3318
A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers. 相似文献