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Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

ABSTRACT: We report the discovery of a novel class of compounds that function as dual inhibitors of the enzymes neutral sphingomyelinase-2 (nSMase2) and acetylcholinesterase (AChE). Inhibition of these enzymes provides a unique strategy to suppress the propagation of tau pathology in the treatment of Alzheimer's disease (AD). We describe the key SAR elements that affect relative nSMase2 and/or AChE inhibitor effects and potency, in addition to the identification of two analogs that suppress the release of tau-bearing exosomes in vitro and in vivo. Identification of these novel dual nSMase2/AChE inhibitors represents a new therapeutic approach to AD and has the potential to lead to the development of truly disease-modifying therapeutics.

SUBMITTER: Bilousova T

PROVIDER: S-EPMC8297715 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

Bilousova Tina T Simmons Bryan J BJ Knapp Rachel R RR Elias Chris J CJ Campagna Jesus J Melnik Mikhail M Chandra Sujyoti S Focht Samantha S Zhu Chunni C Vadivel Kanagasabai K Jagodzinska Barbara B Cohn Whitaker W Spilman Patricia P Gylys Karen H KH Garg Neil K NK John Varghese V

ACS chemical biology 20200514 6

We report the discovery of a novel class of compounds that function as dual inhibitors of the enzymes neutral sphingomyelinase-2 (nSMase2) and acetylcholinesterase (AChE). Inhibition of these enzymes provides a unique strategy to suppress the propagation of tau pathology in the treatment of Alzheimer's disease (AD). We describe the key SAR elements that affect relative nSMase2 and/or AChE inhibitor effects and potency, in addition to the identification of two analogs that suppress the release of ...[more]

PMID: 32352753

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