- Design and synthesis of new potent 5-HT7 receptor ligands as a candidate for the treatment of central nervous system diseases
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Owing to their multifunctional pharmacological profiles (including dual 5-HT1A/5-HT7 action), arylpiperazine derivatives are widely used for treating central nervous system diseases including the depression or neuropathic pain. Herein we describe the design, synthesis and evaluation of biological activity of novel 5-HT7 ligands derived of 2,4,6-triamino-1,3,5-triazine. The studied compounds showed affinity and high selectively towards 5-HT7 receptor with the two most active compounds 34 (Ki = 61 nM), 22 (Ki = 109 nM) showing good metabolic stability and moderate affinity to CYP3A4 isoenzyme. Compound 22 had high hepatotoxicity at a concentration below 50 μM, while compound 34 showed low hepatotoxicity even at a concentration above 50 μM.
- Drabczyk, Anna K.,Latacz, Gniewomir,Ja?kowska, Jolanta,Ku?aga, Damian,Pla?uk, Damian,Rózga, Karolina,Sata?a, Grzegorz
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- Design, synthesis, crystal structure, and herbicidal activity of novel pyrrolidine-2,4-dione derivatives incorporating an alkyl ether pharmacophore with natural tetramic acids as lead compounds
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In order to discover green herbicides with novel molecular scaffolds, natural tetramic acids were used as lead compounds to design and synthesize four pyrrolidine-2,4-dione derivatives incorporating a chainlike alkoxyalkyl moiety (4a-4d) and nineteen pyrrolidine-2,4-dione derivatives incorporating a substituted phenoxyethyl moiety (10a-10s)viasubstitution, acylation, cyclization, and acidification reactions. The synthesized target compounds were confirmed by FT-IR,1H NMR,13C NMR and HRMS spectral analyses. The single-crystal structure of compound10awas analyzed by X-ray diffraction, which revealed that the 1-hydroxyethylidene group links the third position of the pyrrolidine heterocycle through a double bond with theZ-configuration. The herbicidal activity was evaluated using barnyard grass (Echinochloa crus-galli) and rape (Brassica campestris) as model plants by a Petri dish culture method. Most target compounds were found to possess moderate to good inhibitory activities against the plant growth at 100 μg mL?1. Among them, the compounds10qand10nshowed the highest herbicidal activities against the roots of barnyard grass and rape seedlings with the corresponding inhibition rates of 65.6% and 84.0%, respectively. This result indicated that pyrrolidine-2,4-dione derivatives incorporating a substituted phenoxyethyl moiety are worthy of further structural optimization.
- Chen, Min,Geng, Chun-Wen,Han, Ling,Liu, Yu,Yu, Yong-Kai,Lu, Ai-Min,Yang, Chun-Long,Li, Guo-Hua
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p. 5621 - 5630
(2021/04/06)
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- Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1AReceptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
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Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints"that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
- Sniecikowska, Joanna,Gluch-Lutwin, Monika,Bucki, Adam,Wi?ckowska, Anna,Siwek, Agata,Jastrzebska-Wiesek, Magdalena,Partyka, Anna,Wilczyńska, Daria,Pytka, Karolina,Latacz, Gniewomir,Przejczowska-Pomierny, Katarzyna,Wyska, El?bieta,Weso?owska, Anna,Paw?owski, Maciej,Newman-Tancredi, Adrian,Kolaczkowski, Marcin
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supporting information
p. 10946 - 10971
(2020/11/09)
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- Preparation method for 2-(2-methoxyphenoxy)ethylamine
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The invention provides a preparation method for 2-(2-methoxyphenoxy)ethylamine. The preparation method comprises the following steps: synthesizing 2-(2-methoxyphenoxy)ethanol with guaiacol as a starting material; then synthesizing 2-(2-methoxyphenoxy)chloroethane through chlorination; then reacting 2-(2-methoxyphenoxy)chloroethane with potassium phthalimide to obtain N-(o-methoxyphenoxyethyl)-phthalimide; and finally, performing basic hydrolysis to obtain 2-(2-methoxyphenoxy)ethylamine. The yields of the above four steps of reactions are that the yield of 2-(2-methoxyphenoxy)ethanol is 98.9%;the yield of 2-(2-methoxyphenoxy)chloroethane is 93.7%; the yield of N-(o-methoxyphenoxyethyl)-phthalimide is 86.4%; the yield of 2-(2-methoxyphenoxy)ethylamine is 91.2%; and the total yield of the four steps is 73.04%, which is higher than the yield of 43% in conventional production processes. The preparation method of the invention reduces the production cost of 2-(2-methoxyphenoxy)ethylamine and is safe in the production process.
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- Identification of N-Benzyl 3,5-Dinitrobenzamides Derived from PBTZ169 as Antitubercular Agents
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A series of benzamide scaffolds were designed and synthesized by the thiazinone ring opening of PBTZ169, and N-benzyl 3,5-dinitrobenzamides were finally identified as anti-TB agents in this work. 3,5-Dinitrobenzamides D5, 6, 7, and 12 exhibit excellent in vitro activity against the drug susceptive Mycobacterium tuberculosis H37Rv strain (MIC: 0.0625 μg/mL) and two clinically isolated multidrug-resistant strains (MIC 0.016-0.125 μg/mL). Compound D6 displays acceptable safety and better pharmacokinetic profiles than PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery.
- Li, Linhu,Lv, Kai,Yang, Yupeng,Sun, Jingquan,Tao, Zeyu,Wang, Apeng,Wang, Bin,Wang, Hongjian,Geng, Yunhe,Liu, Mingliang,Guo, Huiyuan,Lu, Yu
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supporting information
p. 741 - 745
(2018/07/05)
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- Identification of N-(2-Phenoxyethyl)imidazo[1,2-a]pyridine-3-carboxamides as New Antituberculosis Agents
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A series of imidazo[1,2-a]pyridine carboxamides (IPAs) bearing an N-(2-phenoxyethyl) moiety was designed and synthesized as new antitubercular agents. Seven 2,6-dimethyl IPAs demonstrated excellent in vitro activity (MIC: 0.025-0.054 μg/mL) against the drug susceptive H37Rv strain and two clinically isolated multidrug-resistant Mycobacterium tuberculosisstrains. Compound 10j displayed acceptable safety and pharmacokinetic properties, opening a new direction for further development.
- Wu, Zhaoyang,Lu, Yu,Li, Linhu,Zhao, Rui,Wang, Bin,Lv, Kai,Liu, Mingliang,You, Xuefu
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supporting information
p. 1130 - 1133
(2016/12/16)
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- Design, synthesis, and pharmacological effects of structurally simple ligands for MT1 and MT2 melatonin receptors
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A series of phenoxyalkyl and phenylthioalkyl amides were prepared as melatoninergic ligands. Modulation of affinity of the newly synthesized compound by applying SARs around the terminal amide moiety, the alkyl chain, and the methoxy group on the aromatic ring provides compounds with nanomolar affinity for both melatonin receptor subtypes. Affinity towards MT1 and MT2 receptors were modulated also exploiting chirality. The investigation of intrinsic activity revealed that all the tested compounds behave as full or partial agonists.
- Carocci, Alessia,Catalano, Alessia,Lovece, Angelo,Lentini, Giovanni,Duranti, Andrea,Lucini, Valeria,Pannacci, Marilou,Scaglione, Francesco,Franchini, Carlo
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experimental part
p. 6496 - 6511
(2010/10/02)
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- Synthesis and adrenolytic activity of 1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol and its enantiomers. Part 1
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The synthesis of (2RS)-1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol ((RS)-9) and its enantiomers has been described and tested for electrocardiographic, antiarrhythmic, hypotensive and spasmolytic activities as well as for α1-, α2- and β1-adrenoceptors' binding affinities. All compounds significantly decrease systolic and diastolic blood pressure, and possess antiarrhythmic activity and affinity to α1-, α2- and β1-adrenoceptors. The results suggest that the antiarrhythmic and hypotensive effects of these compounds are related to their adrenolytic but not spasmolytic properties.
- Groszek, Grazyna,Bednarski, Marek,Dybala, Malgorzata,Filipek, Barbara
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experimental part
p. 809 - 817
(2009/09/05)
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- PREPARATION OF 2-(2-ALKOXY PHENOXY) ETHYLAMINE, AN INTERMEDIATE OF CARVEDILOL AND TAMSULOSIN
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The present patent application relates to a process for the preparation of 2-(2-Alkoxy phenoxy) ethylamine or a salt thereof, which is a useful intermediate in the preparation of several active pharmaceutical ingredients including Carvedilol and Tamsulosin. It also provides 2-(2-methoxy phenoxy) ethylamine in solid form.
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Page/Page column 10
(2009/12/02)
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- Synthesis, Screening, and Molecular Modeling of New Potent and Selective Antagonists at the α1d Adrenergic Receptor
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In the present study, more than 75 compounds structurally related to BMY 7378 have been designed and synthesized. Structural variations of each part of the reference molecule have been introduced, obtaining highly selective ligands for the α1d adrenergic receptor. The molecular determinants for selectivity at this receptor are essentially held by the phenyl substituent in the phenylpiperazine moiety. The integration of an extensive SAR analysis with docking simulations using the rhodopsin-based models of the three α1-AR subtypes and of the 5-HT1A receptor provides significant insights into the characterization of the receptor binding sites as well as into the molecular determinants of ligand selectivity at the α1d-AR and the 5-HT1A receptors. The results of multiple copies simultaneous search (MCSS) on the substituted phenylpiperazines together with those of manual docking of compounds BMY 7378 and 69 into the putative binding sites of the α1a-AR, α1b-AR, α1d-AR, and the 5-HT1A receptors suggest that the phenylpiperazine moiety would dock into a site formed by amino acids in helices 3, 4, 5, 6 and extracellular loop 2 (E2), whereas the spirocyclic ring of the ligand docks into a site formed by amino acids of helices 1, 2, 3, and 7. This docking mode is consistent with the SAR data produced in this work. Furthermore, the binding site of the imide moiety does not allow for the simultaneous involvement of the two carbonyl oxygen atoms in H-bonding interactions, consistent with the SAR data, in particular with the results obtained with the lactam derivative 128. The results of docking simulations also suggest that the second and third extracellular loops may act as selectivity filters for the substituted phenylpiperazines. The most potent and selective compounds for α1d adrenergic receptor, i.e., 69 (Rec 26D/038) and 128 (Rec 26D/073), are characterized by the presence of the 2,5-dichlorophenylpiperazine moiety.
- Leonardi, Amedeo,Barlocco, Daniela,Montesano, Federica,Cignarella, Giorgio,Motta, Gianni,Testa, Rodolfo,Poggesi, Elena,Seeber, Michele,De Benedetti, Pier G.,Fanelli, Francesca
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p. 1900 - 1918
(2007/10/03)
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- The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display α-/β-adrenoceptor antagonist and long-acting antihypertensive activities
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A new series of dihydropyridine derivatives, bearing oxypropanolamine moiety on phenyl ring at the 4-position of the dihydropyridine base, were prepared. Oxypropanolamine was synthesized by replacing the phenolic OH of vanillin or other compounds, having a phenyl aldehyde group, with epichlorohydrin, followed by cleavaging the obtained epoxide compounds with tert-butylamine, n-butylamine or 2-methoxy-1-oxyethylamino benzene (guaiacoxyethylamine), respectively. Obtained various oxypropanolamine compounds, still remaining a phenyl aldehyde moiety, were then performed by Hantzsch condensation reaction with methylacetoacetate or ethylacetoacetate, respectively, to give our new series of dihydropyridine linked with the 4-phenyl ring. These compounds were evaluated for inotropic, chronotropic, and aorta contractility that associated with calcium channel and adrenoceptor antagonist activities. Dihydropyridine derivatives that with oxypropanolamine side chain on their 4-phenyl ring associated α-/β-adrenoceptor blocking activities created a new family of calcium entry and the third generation β-adrenoceptor blockers. Optimizing this research to obtain more potent α-/β-adrenoceptor blocking and long-acting antihypertensive oxypropanolamine on the 4-phenyl ring of dihydropyridine series compounds was thus accomplished and classified as third generation dihydropyridine type calcium channel blockers, in comparison with previous short-acting type nifedipine and long-acting type amlodipine. We concluded that compounds 1a, 1b and 1g showed not only markedly high calcium-antagonistic activity but also the highest antihypertensive effect; compounds 1b, 1c, 1f, 1g, 1i and 1j induced sustained antihypertensive effects are major and attributed to their calcium entry and α-adrenoceptor blocking activities in the blood vessel due to their introduction of 2-methoxy, 1-oxyethylamino benzene moiety in the side chain on the 4-phenyl ring of dihydropyridine. Bradycardiac effects of all the compounds 1a-1j resulted from calcium entry and β-adrenoceptor blocking, which attenuate the sympathetic activation-associated reflex tachycardia in the heart. We selected compound 1b as candidate compound for further pharmacological and pre-clinical evaluation studies.
- Liang, Jhy-Chong,Yeh, Jwu-Lai,Wang, Chia-Sui,Liou, Shwu-Fen,Tsai, Chieh-Ho,Chen, Ing-Jun
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p. 719 - 730
(2007/10/03)
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