Discovery of 1,4-Disubstituted 3-Cyano-2-pyridones: A New Class of Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor

详细信息    查看全文

• 作者：Jose Mar铆a Cid ; Guillaume Duvey ; Gary Tresadern ; Vanthea Nhem ; Rocco Furnari ; Philippe Cluzeau ; Juan Antonio Vega ; Ana Isabel de Lucas ; Encarnaci贸n Matesanz ; Jos茅 Manuel Alonso ; Mar铆a Lourdes Linares ; Jos茅 Ignacio Andr茅s ; Sonia M. Poli ; Robert Lutjens ; Hassan Himogai ; Jean-Philippe Rocher ; Gregor J. Macdonald ; Daniel Oehlrich ; Hilde Lavreysen ; Abdelah Ahnaou ; Wilhelmus Drinkenburg ; Claire Mackie ; Andr茅s A. Trabanco
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2388-2405
• 全文大小：667K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

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鈥搘ake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.