Allyl-Assisted, Cu(I)-Catalyzed Azide–Alkyne Cycloaddition/Allylation Reaction: Assembly of the [1,2,3]Triazolo-4,5,6,7-tetrahydropyridine Core Structure

We report a Cu­(I)-catalyzed azide–alkyne–allyl halide three-component reaction for a one-pot synthesis of 1,4-disubstituted 5-allyl-1,2,3-triazoles. The allyl moiety provides not only the electrophile but also a coordinating ligand to Cu, which is essential for the reaction to occur under mild conditions. A concise synthesis of a potential drug candidate <b>1</b> is realized based on this key reaction

Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists

We describe the synthesis and SAR of 1,2,3-triazolopiperidines as a novel series of potent, brain penetrant P2X7 antagonists. Initial efforts yielded a series of potent human P2X7R antagonists with moderate to weak rodent potency, some CYP inhibition, poor metabolic stability, and low solubility. Further work in this series, which focused on the SAR of the <i>N</i>-linked heterocycle, not only increased the potency at the human P2X7R but also provided compounds with good potency at the rat P2X7R. These efforts eventually delivered a potent rat and human P2X7R antagonist with good physicochemical properties, an excellent pharmacokinetic profile, good partitioning into the CNS, and demonstrated in vivo target engagement after oral dosing

Identification of (<i>R</i>)‑(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro‑1<i>H</i>‑imidazo[4,5‑<i>c</i>]pyridin-5(4<i>H</i>)‑yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor

The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo­[4,5-<i>c</i>]­pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo­[4,5-<i>c</i>]­pyridines ultimately leading to the identification of <b>1</b> (JNJ 54166060). <b>1</b> is a potent P2X7 antagonist with an ED₅₀ = 2.3 mg/kg in rats, high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD. Additionally, <b>1</b> possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism

Lead Optimization of 5‑Aryl Benzimidazolone- and Oxindole-Based AMPA Receptor Modulators Selective for TARP γ‑8

Glutamate mediates fast excitatory neurotransmission via ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, we describe the discovery, lead optimization, and preclinical characterization of 5-arylbenzimidazolone and oxindole-based negative modulators of AMPARs associated with TARP γ-8, the primary TARP found in hippocampus. High-throughput screen lead <b>4</b> was optimized for potency and brain penetration to provide benzimidazolone <b>3</b>, JNJ-55511118. Replacement of the benzimidazolone core in <b>3</b> with an oxindole mitigated reactive metabolite formation and led to the identification of <b>18</b> (GluA1/γ-8 pIC₅₀ = 9.7). Following oral dosing in rats, <b>18</b> demonstrated robust target engagement in hippocampus as assessed by <i>ex vivo</i> autoradiography (ED₅₀ = 0.6 mg/kg, plasma EC₅₀ = 9 ng/mL)

4‑Methyl-6,7-dihydro‑4<i>H</i>‑triazolo[4,5‑<i>c</i>]­pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate

The synthesis and preclinical characterization of novel 4-(<i>R</i>)-methyl-6,7-dihydro-4<i>H</i>-triazolo­[4,5-<i>c</i>]­pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4<i>H</i>-triazolo­[4,5-<i>c</i>]­pyridines, methyl substituted 5,6,7,8-tetrahydro­[1,2,4]­triazolo­[4,3-<i>a</i>]­pyrazines, and several other series lead to the identification of a series of 4-(<i>R</i>)-methyl-6,7-dihydro-4<i>H</i>-triazolo­[4,5-<i>c</i>]­pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (<b>14</b>) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein