- MAGL inhibitor as well as preparation method and application thereof
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The invention relates to a compound shown as a formula I in the description and a pharmaceutically acceptable salt thereof, a preparation method, an intermediate for preparing the compound, a composition containing the compound or salt, and application of the compound for preparing drugs for treating MAGL-mediated diseases and symptoms.
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- Discovery of Aryl Formyl Piperidine Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase Inhibitors
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Most of the current monoacylglycerol lipase (MAGL) inhibitors function by an irreversible mechanism of action, causing a series of side effects. Herein, starting from irreversible inhibitors, 25 compounds were synthesized and evaluated in vitro for MAGL inhibition, among which, compound 36 showed the most potent inhibitory activity (IC50 = 15 nM). Crucially, docking studies demonstrated that the m-chlorine-substituted aniline fragment occupied a hydrophobic subpocket enclosed by side chains of Val191, Tyr194, Val270, and Lys273, which creatively identify a new key anchoring point for the development of new MAGL inhibitors. Furthermore, in vivo evaluation innovatively revealed that this reversible inhibitor 36 significantly ameliorated depressive-like behaviors induced by reserpine. To the best of our knowledge, this is the first time that reversible inhibitors of MAGL were developed to support MAGL as a potential therapeutic target for depression.
- Zhi, Zhuoer,Zhang, Wenting,Yao, Jingchun,Shang, Yanguo,Hao, Qingjing,Liu, Zhong,Ren, Yushan,Li, Jie,Zhang, Guimin,Wang, Jinxin
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p. 5783 - 5796
(2020/07/14)
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- Light-Induced Alkylation of (Hetero)aromatic Nitriles in a Transition-Metal-Free C-C-Bond Metathesis
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A light-induced C-C-σ-bond metathesis was achieved through transition-metal-free activation of an unstrained C(sp3)-C(sp3)-σ-bond in 1-benzyl-1,2,3,4-tetrahydroisoquinolines. A photoredox-mediated single-electron oxidation of these precursor amines yield radical cations which undergo a homolytic cleavage of a C(sp3)-C(sp3)-σ-bond rather than the well-known α-C-H-scission. The resulting carbon-centered radicals are used in the ipso-substitution of (hetero)aromatic nitriles proceeding through another single-electron transfer-mediated C-C-bond cleavage and formation.
- Lipp, Benjamin,Lipp, Alexander,Detert, Heiner,Opatz, Till
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supporting information
p. 2054 - 2057
(2017/04/27)
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- N-heterocyclic carbene-catalyzed cross-coupling of aromatic aldehydes with activated alkyl halides
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N-Heterocyclic carbene-catalyzed umpolung of aldehydes followed by their interception with diarylbromomethanes has been reported. This conceptually novel transition-metal-free cross-coupling of aldehydes with alkyl halides works well at low catalyst loadings and under mild reaction conditions leading to the formation of diaryl acetophenone derivatives in good yields. In addition, α-halo ketones and esters can also be used as aldehyde reaction partners.
- Padmanaban, Mohan,Biju, Akkattu T.,Glorius, Frank
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- Synthesis and anticonvulsant activity of some cinnamylpiperazine derivatives
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A series of cinnamylpiperazine derivatives was synthesized using different benzophenone as starting material. The structures of the compounds were proved by their IR, 1H-NMR spectroscopic data and mass spectra data. The anticonvulsant activities of these compounds were evaluated with maximal electroshock (MES) test and rotarod test with intraperitoneal injection on KunMing mice. Among all the flunarizine analogues, no one exhibited better anticonvulsant activity than flunarizine. Flunarizine (4i) exhibited anticonvulsant activity with ED50 of 38.1 mg/kg, TD50 of 164.3 mg/kg and PI of 4.3 through administration intraperitoneal, and with ED50 of 56.8 mg/kg, TD50 of 456.3 mg/kg and PI of 8.0 through oral administration.
- Hu, Chuan,Sun, Zhi-Gang,Wei, Cheng-Xi,Quan, Zhe-Shan
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p. 661 - 664
(2011/11/29)
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- Enantioselective catalytic α-alkylation of aldehydes via an S N1 pathway
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Primary aminothiourea derivatives are shown to catalyze enantioselective alkylation of α-arylpriopionaldehdyes with diarylbromomethane. Evidence for a stepwise, S N1 mechanism in the substitution reaction induced by anion binding to the catalyst is provided by catalyst structure-activity studies, kinetic isotope effects, linear free-energy relationship studies, and competition experiments.
- Brown, Adam R.,Kuo, Wen-Hsin,Jacobsen, Eric N.
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supporting information; experimental part
p. 9286 - 9288
(2010/11/03)
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- MODULATORS OF C3A RECEPTOR AND METHODS OF USE THEREOF
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Provided are compounds that are modulators of C3a receptor activity, compositions containing the compounds and methods of use of the compounds and compositions. In certain embodiments, the compounds are pyridones. In certain embodiments, provided are methods for treatment or amelioration of diseases associated with modulation of C3a receptor activity.
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Page/Page column 99-100
(2008/12/07)
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- Synthesis of 4-fluoro-β(4-fluorophenyl)-l-phenylalanine by an asymmetric phase-transfer catalyzed alkylation: Synthesis on scale and catalyst stability
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4-Fluoro-β-(4-fluorophenyl)-L-phenylalanine 1 was synthesized by the asymmetric phase-transfer catalyzed alkylation of tert-butyl glycinate-benzophenone Schiff base using the cinchona alkaloid derived catalyst 6. Upon scaling, it was observed that to achieve high levels of enantioselectivity, it was necessary to add the catalyst or base last. From these studies, insight into the stability of the catalyst 6 under the reaction conditions was gained.
- Patterson, Daniel E.,Xie, Shiping,Jones, Lynda A.,Osterhout, Martin H.,Henry, Christopher G.,Roper, Thomas D.
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p. 624 - 627
(2012/12/31)
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- Tricyclic compounds, their production and use
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A compound of the formula: wherein R1 is H or a substituent; m is 1-3; Ar is an aromatic group which may be substituted; X is a bond or a divalent straight-chain group having 1-6 atoms which may be substituted; Y is —S—, —O—, or —N(R2— (R2 is H or a substituent group), Z is —N= or —C(R3)= (R3 is H or a hydrocarbon group), ring A is a benzene ring; ring B is a 5- to 7-membered ring which may be substituted, or a salt thereof is useful for eliciting a prostaglandin I2 receptor agonistic effect.
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