Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore

Seto, Masaki; Kakegawa, Keiko; Takami, Kazuaki; Kikuchi, Fumiaki; Yamamoto, Takeshi; Nakamura, Masaru; Daini, Masaki; Murakami, Masataka; Ohashi, Taiki; Kasahara, Takahito; Wang, Junsi; Ikeda, Zenichi; Wada, Y.; Puenner, Florian; Fujii, Takeshi; Inazuka, Masakazu; Sato, Sho; Suzaki, Tomohiko; Oak, Jeong-Ho; Takai, Yuichi; Kohara, Hiroshi; Kimoto, Kouya; Oki, Hideyuki; Mikami, Satoshi; Sasaki, Masahiro; Tanaka, Yasuto

doi:10.1021/acs.jmedchem.1c02078

Cited by 11 publications

(11 citation statements)

References 31 publications

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“…Insightfully, a S1R/cholesterol microdomain has been proposed at the MAM/ER interface via a CARC [ 99 ] signature sequence in TM 1 that may create a lipid/protein “interactome” [ 12 , 98 ]. It should be possible to take advantage of the emergence of ceramide synthases and ceramidases as drug targets [ 63 , 100 , 101 , 102 ] in order to better understand the role(s) of ceramides, SPH, and sphingoid bases as S1R regulators in cellular homeostasis [ 90 ] and in ceramide-related diseased states. The steady-state levels of sphingosine and access to the S1R, therefore, will depend on local ceramide concentrations controlled by dihydroceramide desaturases, sphingomyelinases, ceramide synthases, ceramidases, flipases, methylases, kinases, and phosphatases in the MAM, ER, Golgi-derived, nucleoplasmic reticulum and the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Sphingoid Bases Regulate the Sigma-1 Receptor—Sphingosine and N,N’-Dimethylsphingosine Are Endogenous Agonists

Satyshur

Ruoho

2023

IJMS

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Both bioactive sphingolipids and Sigma-1 receptor (S1R) chaperones occur ubiquitously in mammalian cell membranes. Endogenous compounds that regulate the S1R are important for controlling S1R responses to cellular stress. Herein, we interrogated the S1R in intact Retinal Pigment Epithelial cells (ARPE-19) with the bioactive sphingoid base, sphingosine (SPH), or the pain-provoking dimethylated SPH derivative, N,N-dimethylsphingosine (DMS). As informed by a modified native gel approach, the basal and antagonist (BD-1047)-stabilized S1R oligomers dissociated to protomeric forms in the presence of SPH or DMS (PRE-084 as control). We, thus, posited that SPH and DMS are endogenous S1R agonists. Consistently, in silico docking of SPH and DMS to the S1R protomer showed strong associations with Asp126 and Glu172 in the cupin beta barrel and extensive van der Waals interactions of the C18 alkyl chains with the binding site including residues in helices 4 and 5. Mean docking free energies were 8.73–8.93 kcal/mol for SPH and 8.56–8.15 kcal/mol for DMS, and calculated binding constants were ~40 nM for SPH and ~120 nM for DMS. We hypothesize that SPH, DMS, and similar sphingoid bases access the S1R beta barrel via a membrane bilayer pathway. We further propose that the enzymatic control of ceramide concentrations in intracellular membranes as the primary sources of SPH dictates availability of endogenous SPH and DMS to the S1R and the subsequent control of S1R activity within the same cell and/or in cellular environments.

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Section: Discussionmentioning

confidence: 99%

Sphingoid Bases Regulate the Sigma-1 Receptor—Sphingosine and N,N’-Dimethylsphingosine Are Endogenous Agonists

Satyshur

Ruoho

2023

IJMS

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“…Tanaka and co-workers previously disclosed the structure of T-036 ( 40 , Scheme A) as a potent glucosylceramide synthase (GCS) inhibitor. , In a separate study, the same authors sought to determine the impact on potency and physicochemical profile when the 6-position of the fused pyridyl ring core was functionalized. An LSF strategy was employed to prepare this library of T-036 analogues from the parent compounds 41 and 42 (Scheme A) .…”

Section: Late-stage Functionalization Methodologies To Improve Drug-l...mentioning

confidence: 99%

Late-stage Functionalization for Improving Drug-like Molecular Properties

Castellino,

Montgomery,

Danon

et al. 2023

Chem. Rev.

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The development of late-stage functionalization (LSF) methodologies, particularly C–H functionalization, has revolutionized the field of organic synthesis. Over the past decade, medicinal chemists have begun to implement LSF strategies into their drug discovery programs, allowing for the drug discovery process to become more efficient. Most reported applications of late-stage C–H functionalization of drugs and drug-like molecules have been to rapidly diversify screening libraries to explore structure–activity relationships. However, there has been a growing trend toward the use of LSF methodologies as an efficient tool for improving drug-like molecular properties of promising drug candidates. In this review, we have comprehensively reviewed recent progress in this emerging area. Particular emphasis is placed on case studies where multiple LSF techniques were implemented to generate a library of novel analogues with improved drug-like properties. We have critically analyzed the current scope of LSF strategies to improve drug-like properties and commented on how we believe LSF can transform drug discovery in the future. Overall, we aim to provide a comprehensive survey of LSF techniques as tools for efficiently improving drug-like molecular properties, anticipating its continued uptake in drug discovery programs.

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“…Recent studies reported on the discovery of a new class of GCS inhibitors, obtained by means of high throughput screening (HTS) using a cellular assay measuring the decrease of GlcCer in fibroblasts of GD patients. [118,119] The compounds present a novel chemical structure, distinct from the substrate mimetic inhibitors reported till now. The ligand-based SAR study that allowed to obtain an optimization of the structures starting from T-036 and its derivatives revealed new key pharmacophores for the GCS inhibitory activity.…”

Section: T-036 and Its Optimized Derivativesmentioning

confidence: 99%

Gaucher Disease: A Glance from a Medicinal Chemistry Perspective

Prencipe,

Barzan,

Savian

et al. 2024

ChemMedChem

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Rare diseases are particular pathological conditions affecting a limited number of people and few drugs are known to be effective as therapeutic treatment. Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, belongs to this class of disorders, and it is considered the most common among the Lysosomal Storage Diseases. The two main therapeutic approaches are the Enzyme Replacement Therapy (ERT) and the Substrate Reduction Therapy (SRT). ERT, consisting in replacing the defective enzyme by administering a recombinant enzyme, is effective in alleviating the visceral symptoms, hallmarks of the most common subtype of the disease whereas it has no effects when symptoms involve CNS, since the recombinant protein is unable to significantly cross the Blood Brain Barrier. The SRT strategy involves inhibiting glucosylceramide synthase (GCS), the enzyme responsible for the production of the associated storage molecule. The rational design of new inhibitors of GCS has been hampered by the lack of either the crystal structure of the enzyme or an in‐silico model of the active site which could provide important information regarding the interactions of potential inhibitors with the target, but, despite this, interesting results have been obtained and are herein reviewed.

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Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore

Cited by 11 publications

References 31 publications

Sphingoid Bases Regulate the Sigma-1 Receptor—Sphingosine and N,N’-Dimethylsphingosine Are Endogenous Agonists

Sphingoid Bases Regulate the Sigma-1 Receptor—Sphingosine and N,N’-Dimethylsphingosine Are Endogenous Agonists

Late-stage Functionalization for Improving Drug-like Molecular Properties

Gaucher Disease: A Glance from a Medicinal Chemistry Perspective

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