- 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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- Synthesis and biological evaluation of sphingosine kinase 2 inhibitors with anti-inflammatory activity
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The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly
- Vettorazzi, Marcela,Vila, Laura,Lima, Santiago,Acosta, Lina,Yépes, Felipe,Palma, Alirio,Cobo, Justo,Tengler, Jan,Malik, Ivan,Alvarez, Sergio,Marqués, Patrice,Cabedo, Nuria,Sanz, María J.,Jampilek, Josef,Spiegel, Sarah,Enriz, Ricardo D.
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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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- Synthesis of new (arylcarbonyloxy)aminopropanol derivatives and the determination of their physico-chemical properties
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Eight hydrochlorides of 3-{2-[(2/4-fluorophenoxy)-ethylamino]}-2- hydroxypropyl-4-alkoxybenzoates and four hydrochlorides of 3-tert-butylamino-2- hydroxypropyl-4-butoxybenzoates were prepared as potential antagonists of the β1-adrenergic receptor (beta-blockers). A multistep synthesis of these compounds is described as well as their detailed analytical characterization. The pharmacokinetic properties of these weak base compounds are significantly influenced by their acid-base dissociation constant, pK a. The knowledge of this value is crucial for new drug development. This paper is aimed at developing a methodology that utilizes pH-dependent 1H NMR spectroscopy for its routine analysis. The selected predicted physico-chemical parameters of the new (arylcarbonyloxy)aminopropanols (i.e., aryloxyaminopropanol derivatives) were compared with the model drugs esmolol and flestolol. [Figure not available: see fulltext.]
- Tengler, Jan,Kapustikova, Iva,Stropnicky, Ondrej,Mokry, Petr,Oravec, Michal,Csoellei, Jozef,Jampilek, Josef
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p. 1757 - 1767
(2013/09/23)
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- OXYCARBAMOYL COMPOUNDS AND THE USE THEREOF
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The invention relates to oxycarbamoyl compounds of Formula I: The invention is also directed to the use compounds of Formula I to treat, prevent or ameliorate a disorder responsive to the blockadeof calcium channels, and particularly N-type calcium channe
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- USE OF AMPK-ACTIVATING IMIDAZOLE DERIVATIVES, PREPARATION PROCESS THEREFOR AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
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The invention relates to the use of imidazole derivatives of the formula (I): in which A, R'1, R'2 and R'3 are as defined in the description, as AMPK activators. The invention also relates to processes for the preparation of the said compounds, to their uses for the preparation of medicaments for the treatment of insulin resistance, diabetes and related pathologies, and also obesity, and to the pharmaceutical compositions comprising them. Certain compounds of the formula (I) are novel and, in this respect, also form part of the invention.
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Page/Page column 33
(2008/06/13)
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