1362703-30-7Relevant academic research and scientific papers
1,5,7-TRISUBSTITUTED ISOQUINOLINE DERIVATIVES, PREPARATION THEREOF, AND USE THEREOF IN MEDICINES
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Paragraph 0230; 0232; 0234, (2020/08/30)
The present disclosure relates to 1,5,7-trisubstituted isoquinoline derivatives, their preparation and pharmaceutical use. In particular, the present disclosure discloses a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a preparation method and use thereof. The definitions of the groups in the formula can be found in the specification and claims.
Discovery of 1,4-disubstituted 3-cyano-2-pyridones: A new class of positive allosteric modulators of the metabotropic glutamate 2 receptor
Cid, Jose María,Duvey, Guillaume,Tresadern, Gary,Nhem, Vanthea,Furnari, Rocco,Cluzeau, Philippe,Vega, Juan Antonio,De Lucas, Ana Isabel,Matesanz, Encarnación,Alonso, José Manuel,Linares, María Lourdes,Andrés, José Ignacio,Poli, Sonia M.,Lutjens, Robert,Himogai, Hassan,Rocher, Jean-Philippe,MacDonald, Gregor J.,Oehlrich, Daniel,Lavreysen, Hilde,Ahnaou, Abdelah,Drinkenburg, Wilhelmus,MacKie, Claire,Trabanco, Andrés A.
, p. 2388 - 2405 (2012/05/05)
The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.
