Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease

Michal Šála; Kristen R. Hollinger; Kristen Hollinger; Kristen Hollinger; Ajit G. Thomas; Ranjeet P. Dash; Carolyn Tallon; Carolyn Tallon; Vijayabhaskar Veeravalli; Vijayabhaskar Veeravalli; Lyndah Lovell; Martin Kögler; Hubert Hřebabecký; Eliška Procházková; Ondřej Nešuta; Ondřej Nešuta; Amanda Donoghue; Jenny Lam; Rana Rais; Rana Rais; Camilo Rojas; Camilo Rojas; Barbara S. Slusher; Barbara S. Slusher; Barbara S. Slusher; Barbara S. Slusher; Barbara S. Slusher; Barbara S. Slusher; Barbara S. Slusher; Radim Nencka

doi:10.1021/acs.jmedchem.0c00278

Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease

Michal Šála, Kristen R. Hollinger, Kristen Hollinger, Kristen Hollinger, Ajit G. Thomas, Ranjeet P. Dash, Carolyn Tallon, Carolyn Tallon, Vijayabhaskar Veeravalli, Vijayabhaskar Veeravalli, Lyndah Lovell, Martin Kögler, Hubert Hřebabecký, Eliška Procházková, Ondřej Nešuta, Ondřej Nešuta, Amanda Donoghue, Jenny Lam, Rana Rais, Rana RaisCamilo Rojas, Camilo Rojas, Barbara S. Slusher, Barbara S. Slusher, Barbara S. Slusher, Barbara S. Slusher, Barbara S. Slusher, Barbara S. Slusher, Barbara S. Slusher, Radim Nencka

School of Medicine

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

7 Scopus citations

Abstract

Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is critical for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release have been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate 1 (PDDC), the first nSMase2 inhibitor that possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration, and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate the efficacy of 1 (PDDC) in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogues, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.

Original language	English (US)
Pages (from-to)	6028-6056
Number of pages	29
Journal	Journal of medicinal chemistry
Volume	63
Issue number	11
DOIs	https://doi.org/10.1021/acs.jmedchem.0c00278
State	Published - Jun 11 2020

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.0c00278

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Šála, M., Hollinger, K. R., Hollinger, K., Hollinger, K., Thomas, A. G., Dash, R. P., Tallon, C., Tallon, C., Veeravalli, V., Veeravalli, V., Lovell, L., Kögler, M., Hřebabecký, H., Procházková, E., Nešuta, O., Nešuta, O., Donoghue, A., Lam, J., Rais, R., ... Nencka, R. (2020). Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease. Journal of medicinal chemistry, 63(11), 6028-6056. https://doi.org/10.1021/acs.jmedchem.0c00278

Šála, M, Hollinger, KR, Hollinger, K, Hollinger, K, Thomas, AG, Dash, RP, Tallon, C, Tallon, C, Veeravalli, V, Veeravalli, V, Lovell, L, Kögler, M, Hřebabecký, H, Procházková, E, Nešuta, O, Nešuta, O, Donoghue, A, Lam, J, Rais, R, Rais, R, Rojas, C, Rojas, C, Slusher, BS, Slusher, BS, Slusher, BS, Slusher, BS, Slusher, BS, Slusher, BS, Slusher, BS & Nencka, R 2020, 'Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease', Journal of medicinal chemistry, vol. 63, no. 11, pp. 6028-6056. https://doi.org/10.1021/acs.jmedchem.0c00278

@article{d1d3d7562508496d97c16e6e278fab9e,

title = "Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease",

abstract = "Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is critical for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release have been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate 1 (PDDC), the first nSMase2 inhibitor that possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration, and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate the efficacy of 1 (PDDC) in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogues, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.",

author = "Michal {\v S}{\'a}la and Hollinger, {Kristen R.} and Kristen Hollinger and Kristen Hollinger and Thomas, {Ajit G.} and Dash, {Ranjeet P.} and Carolyn Tallon and Carolyn Tallon and Vijayabhaskar Veeravalli and Vijayabhaskar Veeravalli and Lyndah Lovell and Martin K{\"o}gler and Hubert H{\v r}ebabeck{\'y} and Eli{\v s}ka Proch{\'a}zkov{\'a} and Ond{\v r}ej Ne{\v s}uta and Ond{\v r}ej Ne{\v s}uta and Amanda Donoghue and Jenny Lam and Rana Rais and Rana Rais and Camilo Rojas and Camilo Rojas and Slusher, {Barbara S.} and Slusher, {Barbara S.} and Slusher, {Barbara S.} and Slusher, {Barbara S.} and Slusher, {Barbara S.} and Slusher, {Barbara S.} and Slusher, {Barbara S.} and Radim Nencka",

note = "Funding Information: The project was supported by the Czech Academy of Sciences (RVO Grant 61388963). The work was supported by European Regional Development Fund, OP RDE, Project “Chemical biology for drugging undruggable targets (ChemBioDrug)” (Grant CZ.02.1.01/0.0/0.0/16_019/0000729), National Institutes of Health Grant 5 RO1AGO59799-02, and Tau Pipeline Enabling Program T-PEP-18-579974C. Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = jun,

day = "11",

doi = "10.1021/acs.jmedchem.0c00278",

language = "English (US)",

volume = "63",

pages = "6028--6056",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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T1 - Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease

AU - Šála, Michal

AU - Hollinger, Kristen R.

AU - Hollinger, Kristen

AU - Thomas, Ajit G.

AU - Dash, Ranjeet P.

AU - Tallon, Carolyn

AU - Veeravalli, Vijayabhaskar

AU - Lovell, Lyndah

AU - Kögler, Martin

AU - Hřebabecký, Hubert

AU - Procházková, Eliška

AU - Nešuta, Ondřej

AU - Donoghue, Amanda

AU - Lam, Jenny

AU - Rais, Rana

AU - Rojas, Camilo

AU - Slusher, Barbara S.

AU - Nencka, Radim

N1 - Funding Information: The project was supported by the Czech Academy of Sciences (RVO Grant 61388963). The work was supported by European Regional Development Fund, OP RDE, Project “Chemical biology for drugging undruggable targets (ChemBioDrug)” (Grant CZ.02.1.01/0.0/0.0/16_019/0000729), National Institutes of Health Grant 5 RO1AGO59799-02, and Tau Pipeline Enabling Program T-PEP-18-579974C. Publisher Copyright: © 2020 American Chemical Society.

PY - 2020/6/11

Y1 - 2020/6/11

N2 - Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is critical for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release have been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate 1 (PDDC), the first nSMase2 inhibitor that possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration, and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate the efficacy of 1 (PDDC) in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogues, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.

AB - Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is critical for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release have been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate 1 (PDDC), the first nSMase2 inhibitor that possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration, and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate the efficacy of 1 (PDDC) in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogues, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.

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JO - Journal of medicinal chemistry

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IS - 11

ER -

Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease

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