- Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists
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The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan-1-yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand-based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two-electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl-cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2-chloro-N-[1-(3-(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide (56) exhibiting the best potency with an IC50 value of 0.39 μΜ.
- Durner, Anna,Koufaki, Maria,Kritsi, Eftichia,Nicke, Annette,Papakostas, Alexios,T. Pournara, Dimitra,Zoumpoulakis, Panagiotis
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supporting information
p. 2530 - 2543
(2020/10/19)
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- Potassium channel openers
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Compounds having the formula I: are useful in treating diseases prevented by or ameliorated with potassium channel openers. Also disclosed are potassium channel opening compositions and a method of opening potassium channels in a mammal.
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- Non-covalent thrombin inhibitors featuring P3-heterocycles with P1-bicyclic arginine surrogates
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Novel, potent, and highly selective classes of thrombin inhibitors were identified, which resulted from judicious combination of P4-aromatics and P2-P3-heterocyclic dipeptide surrogates with weakly basic (calcd pKa ～non-basic - 8.6) bicyclic P1-arginine mimics. The design, synthesis, and biological activity of achiral, non-covalent, orally bioavailable inhibitors NC1-NC44 featuring P1-indazoles, benzimidazoles, indoles, benzotriazoles, and aminobenzisoxazoles is disclosed.
- Cui, Jingrong Jean,Araldi, Gian-Luca,Reiner, John E.,Reddy, Komandla Malla,Kemp, Scott J.,Ho, Jonathan Z.,Siev, Daniel V.,Mamedova, Lala,Gibson, Tony S.,Gaudette, John A.,Minami, Nathaniel K.,Anderson, Susanne M.,Bradbury, Annette E.,Nolan, Thomas G.,Semple
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p. 2925 - 2930
(2007/10/03)
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- The Chemistry of Indoles. XXXII. A Facile Synthetic Method for 6-Indolecarbaldehyde, 6-Indolemethanol, and 6-Substituted 1-Hydroxyindoles and Its Application for the Synthesis of a Natural Alkaloid, (E)-6-(3-Methylbuta-1,3-dienyl)indole
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Trivalent titanium ion can reduce arylaldehydes, and the reaction is controllable by selecting the pH of the reaction medium.Utilizing this new finding, 6-indolecarbaldehyde and 6-indolemethanol were conveniently produced by the modified Leimgruber-Batcho method with titanium(III) chloride as the reducing agent.Syntheses of a natural alkaloid, (E)-6-(3-methylbuta-1,3-dienyl)indole, and some new 6-substituted 1-hydroxyindoles are also reported.Keywords-titanium(III) chloride; 6-indolecarbaldehyde; 6-indolemethanol; (E)-6-(3-methylbuta-1,3-dienyl)indole; (Z)-6-(3-methylbuta-1,3-dienyl)indole; 1-hydroxy-6-indolecarbaldehyde; 1-methoxy-6-indolecerbaldehyde; 1-acetoxy-6-indolecarbaldehyde; Leimgruber-Batcho method; reduction
- Somei, Masanori
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p. 4109 - 4115
(2007/10/02)
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