title: 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).
abstract: 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.
authors: Janssen Research & Development, a Division of Janssen-Cilag, S.A., Toledo 45007, Spain.
authors: Jose María
authors: JM
authors: Cid
authors: Janssen Research & Development, a Division of Janssen-Cilag, S.A., Toledo 45007, Spain.
authors: Gary
authors: G
authors: Tresadern
authors: Janssen Research & Development, a Division of Janssen-Cilag, S.A., Toledo 45007, Spain.
authors: Juan Antonio
authors: JA
authors: Vega
authors: Janssen Research & Development, a Division of Janssen-Cilag, S.A., Toledo 45007, Spain.
authors: Ana Isabel
authors: AI
authors: de Lucas
authors: Janssen Research & Development, a Division of Janssen-Cilag, S.A., Toledo 45007, Spain.
authors: Alcira
authors: A
authors: Del Cerro
authors: Janssen Research & Development, a Division of Janssen-Cilag, S.A., Toledo 45007, Spain.
authors: Encarnación
authors: E
authors: Matesanz
authors: Janssen Research & Development, a Division of Janssen-Cilag, S.A., Toledo 45007, Spain.
authors: María Lourdes
authors: ML
authors: Linares
authors: Janssen Research & Development, a Division of Janssen-Cilag, S.A., Toledo 45007, Spain.
authors: Aránzazu
authors: A
authors: García
authors: Janssen Research & Development, a Division of Janssen-Cilag, S.A., Toledo 45007, Spain.
authors: Laura
authors: L
authors: Iturrino
authors: Laboratori de Medicina Computacional Unitat de Bioestadistica, Facultat de Medicina, Universitat Autonoma de Barcelona , Bellaterra 08193, Spain.
authors: Laura
authors: L
authors: Pérez-Benito
authors: Janssen Research & Development, Janssen Pharmaceutica NV, Beerse B-2340, Belgium.
authors: Gregor J
authors: GJ
authors: Macdonald
authors: Janssen Research & Development, Janssen Pharmaceutica NV, Beerse B-2340, Belgium.
authors: Daniel
authors: D
authors: Oehlrich
authors: Janssen Research & Development, Janssen Pharmaceutica NV, Beerse B-2340, Belgium.
authors: Hilde
authors: H
authors: Lavreysen
authors: Janssen Research & Development, Janssen Pharmaceutica NV, Beerse B-2340, Belgium.
authors: Luc
authors: L
authors: Peeters
authors: Janssen Research & Development, Janssen Pharmaceutica NV, Beerse B-2340, Belgium.
authors: Marc
authors: M
authors: Ceusters
authors: Janssen Research & Development, Janssen Pharmaceutica NV, Beerse B-2340, Belgium.
authors: Abdellah
authors: A
authors: Ahnaou
authors: Janssen Research & Development, Janssen Pharmaceutica NV, Beerse B-2340, Belgium.
authors: Wilhelmus
authors: W
authors: Drinkenburg
authors: Janssen Research & Development, Janssen Pharmaceutica NV, Beerse B-2340, Belgium.
authors: Claire
authors: C
authors: Mackie
authors: Janssen Research & Development, Janssen Pharmaceutica NV, Beerse B-2340, Belgium.
authors: Marijke
authors: M
authors: Somers
authors: Janssen Research & Development, a Division of Janssen-Cilag, S.A., Toledo 45007, Spain.
authors: Andrés A
authors: AA
authors: Trabanco
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D018938:Caco-2 Cells; D003412:Cricetulus; D004285:Dogs; D006801:Humans; D008297:Male; D008958:Models, Molecular; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C439166:1,2,4-triazolo(3,4-a)pyridine; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D014230:Triazoles; C108822:metabotropic glutamate receptor 2