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Savall BM, Wu D, De Angelis M, et al. Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists. ACS Med Chem Lett. 2015;6(6):671-6doi: 10.1021/acsmedchemlett.5b00089.
Savall, B. M., Wu, D., De Angelis, M., Carruthers, N. I., Ao, H., Wang, Q., Lord, B., Bhattacharya, A., & Letavic, M. A. (2015). Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists. ACS medicinal chemistry letters, 6(6), 671-6. https://doi.org/10.1021/acsmedchemlett.5b00089
Savall, Brad M, et al. "Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists." ACS medicinal chemistry letters vol. 6,6 (2015): 671-6. doi: https://doi.org/10.1021/acsmedchemlett.5b00089
Savall BM, Wu D, De Angelis M, Carruthers NI, Ao H, Wang Q, Lord B, Bhattacharya A, Letavic MA. Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists. ACS Med Chem Lett. 2015 Apr 24;6(6):671-6. doi: 10.1021/acsmedchemlett.5b00089. eCollection 2015 Jun 11. PMID: 26101572; PMCID: PMC4468405.
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ACS Med Chem Lett. 2015 Apr 24;6(6):671-6. doi: 10.1021/acsmedchemlett.5b00089. eCollection 2015 Jun 11.

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

ACS medicinal chemistry letters

Brad M Savall, Duncan Wu, Meri De Angelis, Nicholas I Carruthers, Hong Ao, Qi Wang, Brian Lord, Anindya Bhattacharya, Michael A Letavic

Affiliations

  1. Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
  2. Janssen Research & Development , Discovery Sciences, a division of Janssen-Cilag, Jarama 75, 45007 Toledo, Spain.

PMID: 26101572 PMCID: PMC4468405 DOI: 10.1021/acsmedchemlett.5b00089

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.

Keywords: P2X7; depression; neuro-inflammation

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