Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist

Shane M. Wilkinson; Melissa L. Barron; James O'Brien-Brown; Bieneke Janssen; Leanne Stokes; Eryn L. Werry; Mansoor Chishty; Kristen K. Skarratt; Jennifer A. Ong; David E. Hibbs; Danielle J. Vugts; Stephen Fuller; Albert D. Windhorst; Michael Kassiou

doi:https://doi.org/10.1021/acschemneuro.7b00272

Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X₇ Receptor Antagonist

Shane M. Wilkinson, Melissa L. Barron, James O'Brien-Brown, Bieneke Janssen, Leanne Stokes, Eryn L. Werry, Mansoor Chishty, Kristen K. Skarratt, Jennifer A. Ong, David E. Hibbs, Danielle J. Vugts, Stephen Fuller, Albert D. Windhorst, Michael Kassiou

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

31 Citations (Scopus)

Abstract

Adamantanyl benzamide 1 was identified as a potent P2X₇R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2X₇R antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability. Trifluorinated benzamide 34 demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide 1), and an improved physicokinetic profile and proved effective in the presence of several known P2X₇R polymorphisms.

Original language	English
Pages (from-to)	2374-2380
Number of pages	7
Journal	ACS Chemical Neuroscience
Volume	8
Issue number	11
DOIs	https://doi.org/10.1021/acschemneuro.7b00272
Publication status	Published - 15 Nov 2017

Keywords

P2X
bioisostere
central nervous system (CNS)
metabolism
pharmacokinetic
single nucleotide polymorphisms (SNPs)

Access to Document

https://doi.org/10.1021/acschemneuro.7b00272

Cite this

Wilkinson, S. M., Barron, M. L., O'Brien-Brown, J., Janssen, B., Stokes, L., Werry, E. L., Chishty, M., Skarratt, K. K., Ong, J. A., Hibbs, D. E., Vugts, D. J., Fuller, S., Windhorst, A. D., & Kassiou, M. (2017). Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X₇ Receptor Antagonist. ACS Chemical Neuroscience, 8(11), 2374-2380. https://doi.org/10.1021/acschemneuro.7b00272

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title = "Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist",

abstract = "Adamantanyl benzamide 1 was identified as a potent P2X7R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2X7R antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability. Trifluorinated benzamide 34 demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide 1), and an improved physicokinetic profile and proved effective in the presence of several known P2X7R polymorphisms.",

keywords = "P2X, bioisostere, central nervous system (CNS), metabolism, pharmacokinetic, single nucleotide polymorphisms (SNPs)",

author = "Wilkinson, {Shane M.} and Barron, {Melissa L.} and James O'Brien-Brown and Bieneke Janssen and Leanne Stokes and Werry, {Eryn L.} and Mansoor Chishty and Skarratt, {Kristen K.} and Ong, {Jennifer A.} and Hibbs, {David E.} and Vugts, {Danielle J.} and Stephen Fuller and Windhorst, {Albert D.} and Michael Kassiou",

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Wilkinson, SM, Barron, ML, O'Brien-Brown, J, Janssen, B, Stokes, L, Werry, EL, Chishty, M, Skarratt, KK, Ong, JA, Hibbs, DE, Vugts, DJ, Fuller, S, Windhorst, AD & Kassiou, M 2017, 'Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X₇ Receptor Antagonist', ACS Chemical Neuroscience, vol. 8, no. 11, pp. 2374-2380. https://doi.org/10.1021/acschemneuro.7b00272

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AU - Barron, Melissa L.

AU - O'Brien-Brown, James

AU - Janssen, Bieneke

AU - Stokes, Leanne

AU - Werry, Eryn L.

AU - Chishty, Mansoor

AU - Skarratt, Kristen K.

AU - Ong, Jennifer A.

AU - Hibbs, David E.

AU - Vugts, Danielle J.

AU - Fuller, Stephen

AU - Windhorst, Albert D.

AU - Kassiou, Michael

PY - 2017/11/15

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AB - Adamantanyl benzamide 1 was identified as a potent P2X7R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2X7R antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability. Trifluorinated benzamide 34 demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide 1), and an improved physicokinetic profile and proved effective in the presence of several known P2X7R polymorphisms.

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