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.

Covalent Allosteric Probe for the Metabotropic Glutamate Receptor 2: Design, Synthesis, and Pharmacological Characterization

“…On the basis of a series of analogues of 3-(cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3- a ]pyridine ( 1 , JNJ-46281222), 24 we recently developed a novel series of mGlu 2 PAMs bearing the 7-aryl-1,2,4-triazolo[4,3- a ]pyridine as the core structure. 13,17 This scaffold was used to design three novel putative covalent mGlu 2 PAMs for which the fluorosulfonyl moiety was chosen as a reactive warhead.…”

A concise method for fully automated radiosyntheses of [18F]JNJ-46356479 and [18F]FITM via Cu-mediated 18F-fluorination of organoboranes

“…Chemistry JNJ-46356479 was reported by Cid et al as a potent mGluR2 positive allosteric modulator (PAM) (i.e., EC 50 ¼ 78 nM, E max ¼ 256%) with favorable physiochemical and pharmacological properties as well as CNS-penetrant. 25 JNJ-46356479 has also been established as a selective blocking reagent to characterize the mGluR2 radioligand of [ 11 C]JNJ42491293 in rats and nonhuman primates. 26 Hence, 18 F-radiolabeled JNJ-46356479 is an attractive mGluR2 PET radiotracer if produced in high molar activity using a fully automated platform.…”

“…The synthesis of non-labeled JNJ-46356479 was achieved via the method reported by Cid et al , starting from 2,4-dichloro-3-(trifluoromethyl) pyridine using over 6 steps to allow final reductive coupling reaction between aldehyde 1 and 1-(2,4-difluorophenyl) piperazine 2 ( Scheme 1 ). 25 The para -aryl fluoride of JNJ-46356479 was selected as a radiolabeling site to avoid steric hinderance when introducing 18 F or bulky leaving groups. Traditional nucleophilic S N Ar substitution of nitro- or iodo-leaving groups was assumed not to be feasible due to the poor activating effect of adjacent fluoride.…”

Recent advances in the medicinal chemistry of group II and group III mGlu receptors

“…Finally, they found a potent, orally bioavailable, soluble and selective triazolopyridine class in 2016. Compound 15 (JNJ-46356479), 42 with an EC 50 value of 78 nM using the [ 35 S] GTPγS binding assay, exhibited a lower clearance, higher oral exposure, and higher bioavailability in rodent and nonrodent species, and was thus considered as an attractive agent to explain the role of selective mGlu 2 PAM ( Fig. 7).…”