A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate

Abstract

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders.

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

“…Novel fused triazole 6-methyl-4,5,6,7-tetrahydro-1H- [1,2,3]triazolo [4,5-c]pyridine derivatives were synthesised as P2X7 receptor antagonists by Chrovian et al 138 The 1,2,3-triazole-fused lead 109 (Fig. 14) increased the plasma free fraction that exhibited potential P2X7 receptor occupancy in the hippocampus of rats, with a low ED 50 value of 0.07 mg/kg, and unbound plasma EC 50 value of 12 ng/mL.…”

Recent Advances in CNS P2X7 Physiology and Pharmacology: Focus on Neuropsychiatric Disorders

“…Significant progress has been made toward identification of brain-penetrant P2X7 antagonists. This spans medicinal chemistry efforts from identification of tool molecules to selection of brain-penetrant clinical candidates JNJ-54175446 ( Letavic et al, 2017 ) and JNJ-55308942 ( Chrovian et al, 2017 ). Unlike the Pfizer and AstraZeneca clinical compounds ( Figure 1 ), the Janssen molecules retain rodent activity providing the discovery team to develop robust target engagement assays to drive the chemistry program; in addition, rodent activity provided the team with an opportunity to test the molecules in rodent models of disease, an important missing link in the prior two clinical compounds (CE-224,535 and AZD-9056).…”

“…The discovery of the clinical compound JNJ-54175446 ( Figure 1 ; NCT02902601) and JNJ-55308942 ( Figure 1 ; NCT03151486) is described in detail by Letavic et al (2017) and Chrovian et al (2017) . JNJ-54175446 is a high affinity (and potency) P2X7 antagonist that displays pharmacology at recombinant human, rat, mouse, macaque, and dog P2X7.…”

18F-JNJ-64413739, a Novel PET Ligand for the P2X7 Ion Channel: Radiation Dosimetry, Kinetic Modeling, Test-Retest Variability, and Occupancy of the P2X7 Antagonist JNJ-54175446

“…We report the clinical qualification of 18 F-JNJ-64413739, a selective P2X7 antagonist that was previously extensively evaluated in preclinical models as a candidate PET ligand for P2X7, showing high affinity and selectivity (22). This study includes the dosimetry of 18 F-JNJ-64413739, tracer kinetic modeling optimization with testretest variability (TRV) , and in vivo CNS blocking by pharmacologic doses of the P2X7 antagonist JNJ-54175446 (23,24).…”