Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation

Laura McAllister; Christopher Butler; Scot  Mente; Steven V. O'Neil; Kari  Fonseca; Justin Piro; Julie  Cianfrogna; Timothy Foley; Adam Gilbert; Anthony Harris; Christopher J.  Helal; Douglas S.  Johnson; Justin I.  Montgomery; Deane M.  Nason; Stephen  Noell; Jayvardhan  Pandit; Bruce N.  Rogers; Tarek A.  Samad; Christopher L.  Shaffer; Rafael G. da Silva; Daniel P.  Uccello; Damien  Webb; Michael A.  Brodney

doi:10.1021/acs.jmedchem.8b00070

Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation

Laura McAllister, Christopher Butler, Scot Mente, Steven V. O'Neil, Kari Fonseca, Justin Piro, Julie Cianfrogna, Timothy Foley, Adam Gilbert, Anthony Harris, Christopher J. Helal, Douglas S. Johnson, Justin I. Montgomery, Deane M. Nason, Stephen Noell, Jayvardhan Pandit, Bruce N. Rogers, Tarek A. Samad, Christopher L. Shaffer, Rafael G. da SilvaDaniel P. Uccello, Damien Webb, Michael A. Brodney

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

Abstract

Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.

Original language	English
Pages (from-to)	3008–3026
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	7
Early online date	2 Mar 2018
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00070
Publication status	Published - 12 Apr 2018

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10.1021/acs.jmedchem.8b00070

Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation (PDB entry 6BQ0)
McAllister, L. (Creator), Butler, C. (Creator), Mente, S. (Creator), O'Neil (Steven Neil), S. V. (Creator), Fonseca, K. (Creator), Piro, J. (Creator), Cianfrogna, J. (Creator), Foley, T. (Creator), Gilbert, A. (Creator), Harris, A. (Creator), Helal, C. J. (Creator), Johnson, D. S. (Creator), Montgomery, J. I. (Creator), Nason, D. M. (Creator), Noell, S. (Creator), Pandit, J. (Creator), Rogers, B. N. (Creator), Samad, T. A. (Creator), Shaffer, C. L. (Creator), Guimaraes da Silva, R. (Creator), Uccello, D. P. (Creator), Webb, D. (Creator) & Brodney, M. A. (Creator), Protein Data Bank (PDB), 14 Mar 2018
DOI: 10.2210/pdb6BQ0/pdb, https://www.rcsb.org/structure/6BQ0
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McAllister, L., Butler, C., Mente, S., O'Neil, S. V., Fonseca, K., Piro, J., Cianfrogna, J., Foley, T., Gilbert, A., Harris, A., Helal, C. J., Johnson, D. S., Montgomery, J. I., Nason, D. M., Noell, S., Pandit, J., Rogers, B. N., Samad, T. A., Shaffer, C. L., ... Brodney, M. A. (2018). Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation. Journal of Medicinal Chemistry, 61(7), 3008–3026. https://doi.org/10.1021/acs.jmedchem.8b00070

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title = "Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation",

abstract = "Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.",

author = "Laura McAllister and Christopher Butler and Scot Mente and O'Neil, {Steven V.} and Kari Fonseca and Justin Piro and Julie Cianfrogna and Timothy Foley and Adam Gilbert and Anthony Harris and Helal, {Christopher J.} and Johnson, {Douglas S.} and Montgomery, {Justin I.} and Nason, {Deane M.} and Stephen Noell and Jayvardhan Pandit and Rogers, {Bruce N.} and Samad, {Tarek A.} and Shaffer, {Christopher L.} and {da Silva}, {Rafael G.} and Uccello, {Daniel P.} and Damien Webb and Brodney, {Michael A.}",

year = "2018",

month = apr,

day = "12",

doi = "10.1021/acs.jmedchem.8b00070",

language = "English",

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McAllister, L, Butler, C, Mente, S, O'Neil, SV, Fonseca, K, Piro, J, Cianfrogna, J, Foley, T, Gilbert, A, Harris, A, Helal, CJ, Johnson, DS, Montgomery, JI, Nason, DM, Noell, S, Pandit, J, Rogers, BN, Samad, TA, Shaffer, CL, da Silva, RG, Uccello, DP, Webb, D & Brodney, MA 2018, 'Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation', Journal of Medicinal Chemistry, vol. 61, no. 7, pp. 3008–3026. https://doi.org/10.1021/acs.jmedchem.8b00070

TY - JOUR

T1 - Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation

AU - McAllister, Laura

AU - Butler, Christopher

AU - Mente, Scot

AU - O'Neil, Steven V.

AU - Fonseca, Kari

AU - Piro, Justin

AU - Cianfrogna, Julie

AU - Foley, Timothy

AU - Gilbert, Adam

AU - Harris, Anthony

AU - Helal, Christopher J.

AU - Johnson, Douglas S.

AU - Montgomery, Justin I.

AU - Nason, Deane M.

AU - Noell, Stephen

AU - Pandit, Jayvardhan

AU - Rogers, Bruce N.

AU - Samad, Tarek A.

AU - Shaffer, Christopher L.

AU - da Silva, Rafael G.

AU - Uccello, Daniel P.

AU - Webb, Damien

AU - Brodney, Michael A.

PY - 2018/4/12

Y1 - 2018/4/12

N2 - Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.

AB - Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.

U2 - 10.1021/acs.jmedchem.8b00070

DO - 10.1021/acs.jmedchem.8b00070

M3 - Article

SN - 0022-2623

VL - 61

SP - 3008

EP - 3026

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 7

ER -

Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation

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Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation (PDB entry 6BQ0)

Cite this