Exploration of Alternative Scaffolds for P2Y14Receptor Antagonists Containing a Biaryl Core

Young Hwan Jung, Jinha Yu, Zhiwei Wen, Veronica Salmaso, Tadeusz P. Karcz, Ngan B. Phung, Zhoumou Chen, Sierra Duca, John M. Bennett, Steven Dudas, Daniela Salvemini, Zhan Guo Gao, Donald N. Cook, Kenneth A. Jacobson

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y14 receptor (P2Y14R) antagonists were synthesized, and affinity was measured in P2Y14R-expressing Chinese hamster ovary cells by flow cytometry. Given this series' low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central m-benzoic acid core (25) provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2Y14R region is predicted by homology modeling as a deep, sterically limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic-substituted piperidine ring derivatives of naphthalene antagonist 1, e.g., quinuclidine 17 (MRS4608, IC50 ≈ 20 nM at hP2Y14R/mP2Y14R), or of triazole 2, preserved affinity. Potent antagonists 1, 7a, 17, and 23 (10 mg/kg) protected in an ovalbumin/Aspergillus mouse asthma model, and PEG conjugate 12 reduced chronic pain. Thus, we expanded P2Y14R antagonist structure-activity relationship, introducing diverse physical-chemical properties.

Original languageEnglish
Pages (from-to)9563-9589
Number of pages27
JournalJournal of Medicinal Chemistry
Volume63
Issue number17
DOIs
StatePublished - 10 Sep 2020

Bibliographical note

Funding Information:
We acknowledge support from the NIDDK (ZIA DK031116) and NIEHS (ZIAES102025) Intramural Research Programs and from Kantum Diagnostics (Belmont, NH). We thank Bryan L. Roth, National Institute of Mental Health’s Psychoactive Drug Screening Program (Univ. North Carolina at Chapel Hill, Contract #HHSN-271-2008-00025-C) for screening data. We thank Dr. John Lloyd (NIDDK) for MS spectra and Dr. Jeff Reece (NIDDK Advanced Light Microscopy and Imaging Analysis Core, ALMIAC). This work utilized the computational resources of the NIH HPC Biowulf cluster ( http://hpc.nih.gov ).

Publisher Copyright:
Copyright © 2020 American Chemical Society.

Fingerprint

Dive into the research topics of 'Exploration of Alternative Scaffolds for P2Y14Receptor Antagonists Containing a Biaryl Core'. Together they form a unique fingerprint.

Cite this