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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2015 Jun 24

PMID 26101572

Citations 7

Authors

Brad M Savall

Duncan Wu

Meri De Angelis

Nicholas I Carruthers

Hong Ao

Qi Wang

Brian Lord

Anindya Bhattacharya

Michael A Letavic

Affiliations

Soon will be listed here.

Abstract

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 N-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.

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