TY - JOUR
T1 - 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)
AU - Cid, Jose María
AU - Tresadern, Gary
AU - Vega, Juan Antonio
AU - De Lucas, Ana Isabel
AU - Del Cerro, Alcira
AU - Matesanz, Encarnación
AU - Linares, María Lourdes
AU - García, Aránzazu
AU - Iturrino, Laura
AU - Pérez-Benito, Laura
AU - Macdonald, Gregor J.
AU - Oehlrich, Daniel
AU - Lavreysen, Hilde
AU - Peeters, Luc
AU - Ceusters, Marc
AU - Ahnaou, Abdellah
AU - Drinkenburg, Wilhelmus
AU - Mackie, Claire
AU - Somers, Marijke
AU - Trabanco, Andrés A.
PY - 2016/9/22
Y1 - 2016/9/22
N2 - © 2016 American Chemical Society. 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.
AB - © 2016 American Chemical Society. 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.
U2 - 10.1021/acs.jmedchem.6b00913
DO - 10.1021/acs.jmedchem.6b00913
M3 - Article
VL - 59
SP - 8495
EP - 8507
IS - 18
ER -