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

doi:10.1021/acs.jmedchem.0c00745

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

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

18 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 language	English
Pages (from-to)	9563-9589
Number of pages	27
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.0c00745
State	Published - 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.

Access to Document

10.1021/acs.jmedchem.0c00745

Cite this

Jung, Y. H., Yu, J., Wen, Z., Salmaso, V., Karcz, T. P., Phung, N. B., Chen, Z., Duca, S., Bennett, J. M., Dudas, S., Salvemini, D., Gao, Z. G., Cook, D. N., & Jacobson, K. A. (2020). Exploration of Alternative Scaffolds for P2Y₁₄Receptor Antagonists Containing a Biaryl Core. Journal of Medicinal Chemistry, 63(17), 9563-9589. https://doi.org/10.1021/acs.jmedchem.0c00745

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title = "Exploration of Alternative Scaffolds for P2Y14Receptor Antagonists Containing a Biaryl Core",

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.",

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

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{\textquoteright}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 {\textcopyright} 2020 American Chemical Society.",

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doi = "10.1021/acs.jmedchem.0c00745",

language = "English",

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AU - Jung, Young Hwan

AU - Yu, Jinha

AU - Wen, Zhiwei

AU - Salmaso, Veronica

AU - Karcz, Tadeusz P.

AU - Phung, Ngan B.

AU - Chen, Zhoumou

AU - Duca, Sierra

AU - Bennett, John M.

AU - Dudas, Steven

AU - Salvemini, Daniela

AU - Gao, Zhan Guo

AU - Cook, Donald N.

AU - Jacobson, Kenneth A.

N1 - 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.

PY - 2020/9/10

Y1 - 2020/9/10

N2 - 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.

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