920285-22-9Relevant academic research and scientific papers
Fragment Based Optimization of Metabotropic Glutamate Receptor 2 (mGluR2) Positive Allosteric Modulators in the Absence of Structural Information
Szabó, Gy?rgy,Túrós, Gy?rgy I.,Kolok, Sándor,Vastag, Mónika,Sánta, Zsuzsanna,Dékány, Miklós,Lévay, Gy?rgy I.,Greiner, István,Natsumi, Minami,Tatsuya, Watanabe,Keseru, Gy?rgy M.
, p. 234 - 246 (2019)
Metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators (PAMs) have been implicated as potential pharmacotherapy for psychiatric conditions. Screening our corporate compound deck, we identified a benzotriazole fragment (4) that was rapidly optimized to a potent and metabolically stable early lead (16). The highly lipophilic character of 16, together with its limited solubility, permeability, and high protein binding, however, did not allow reaching of the proof of concept in vivo. Since further attempts on the optimization of druglike properties were unsuccessful, the original hit 4 has been revisited and was optimized following the principles of fragment based drug discovery (FBDD). Lacking structural information on the receptor-ligand complex, we implemented a group efficiency (GE) based strategy and identified a new fragment like lead (60) with more balanced profile. Significant improvement achieved on the druglike properties nominated the compound for in vivo proof of concept studies that revealed the chemotype being a promising PAM lead targeting mGluR2 receptors.
Benzimidazolone and dihydroindolone derivatives and uses thereof
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Page/Page column 65, (2008/06/13)
Compounds of the formula I: or pharmaceutically acceptable salts thereof wherein m, n, X, Ar, R1, R2, R3, R4 and R5 are as defined herein. Also provided are methods for preparing, compositions comprising, and methods for using compounds of formula I.
