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Discovery of 8‑Trifluoromethyl-3-cyclopropylmethyl-7-[(4-(2,4-difluorophenyl)-1-piperazinyl)­methyl]-1,2,4-triazolo[4,3‑a]pyridine (JNJ-46356479), a Selective and Orally Bioavailable mGlu2 Receptor Positive Allosteric Modulator (PAM)

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journal contribution
posted on 2016-08-31, 00:00 authored by Jose María Cid, Gary Tresadern, Juan Antonio Vega, Ana Isabel de Lucas, Alcira del Cerro, Encarnación Matesanz, María Lourdes Linares, Aránzazu García, Laura Iturrino, Laura Pérez-Benito, Gregor J. Macdonald, Daniel Oehlrich, Hilde Lavreysen, Luc Peeters, Marc Ceusters, Abdellah Ahnaou, Wilhelmus Drinkenburg, Claire Mackie, Marijke Somers, Andrés A. Trabanco
Positive allosteric modulators of the metabotropic glutamate 2 receptor have generated great interest in the past decade. There is mounting evidence of their potential as therapeutic agents in the treatment of multiple central nervous system disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs. However, finding compounds with the optimal combination of in vitro potency and good druglike properties has remained elusive, in part because of the hydrophobic nature of the allosteric binding site. Herein, we report on the lead optimization process to overcome the poor solubility inherent to the advanced lead 6. Initial prototypes already showed significant improvements in solubility while retaining good functional activity but displayed new liabilities associated with metabolism and hERG inhibition. Subsequent subtle modifications efficiently addressed those issues leading to the identification of compound 27 (JNJ-46356479). This new lead represents a more balanced profile that offers a significant improvement on the druglike attributes compared to previously reported leads.