FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2954284623> ?p ?o ?g. }

• W2954284623 endingPage "3870" @default.
• W2954284623 startingPage "3857" @default.
• W2954284623 abstract "Extracellular vesicles (EVs) are constitutively shed from cells and released by various stimuli. Their protein and RNA cargo are modified by the stimulus, and in disease conditions can carry pathological cargo involved in disease progression. Neutral sphingomyelinase 2 (nSMase2) is a major regulator in at least one of several independent routes of EV biogenesis, and its inhibition is a promising new therapeutic approach for neurological disorders. Unfortunately, known inhibitors exhibit μM potency, poor physicochemical properties, and/or limited brain penetration. Here, we sought to identify a drug-like inhibitor of nSMase2.We conducted a human nSMase2 high throughput screen (>365,000 compounds). Selected hits were optimized focusing on potency, selectivity, metabolic stability, pharmacokinetics, and ability to inhibit EV release in vitro and in vivo.We identified phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-carbamate (PDDC), a potent (pIC50 = 6.57) and selective non-competitive inhibitor of nSMase2. PDDC was metabolically stable, with excellent oral bioavailability (%F = 88) and brain penetration (AUCbrain /AUCplasma = 0.60). PDDC dose-dependently (pEC50 = 5.5) inhibited release of astrocyte-derived extracellular vesicles (ADEV). In an in vivo inflammatory brain injury model, PDDC robustly inhibited ADEV release and the associated peripheral immunological response. A closely related inactive PDDC analogue was ineffective.PDDC is a structurally novel, potent, orally available, and brain penetrant inhibitor of nSMase2. PDDC inhibited release of ADEVs in tissue culture and in vivo. PDDC is actively being tested in animal models of neurological disease and, along with closely related analogues, is being considered for clinical translation." @default.
• W2954284623 created "2019-07-12" @default.
• W2954284623 creator A5002913273 @default.
• W2954284623 creator A5019482739 @default.
• W2954284623 creator A5022491794 @default.
• W2954284623 creator A5023686004 @default.
• W2954284623 creator A5025729175 @default.
• W2954284623 creator A5029115319 @default.
• W2954284623 creator A5039409144 @default.
• W2954284623 creator A5048687448 @default.
• W2954284623 creator A5068675942 @default.
• W2954284623 creator A5078466007 @default.
• W2954284623 creator A5090359406 @default.
• W2954284623 date "2019-09-04" @default.
• W2954284623 modified "2023-10-17" @default.
• W2954284623 title "A novel and potent brain penetrant inhibitor of extracellular vesicle release" @default.
• W2954284623 cites W1511544167 @default.
• W2954284623 cites W1593555249 @default.
• W2954284623 cites W1594863916 @default.
• W2954284623 cites W1762620449 @default.
• W2954284623 cites W1971233854 @default.
• W2954284623 cites W1991931811 @default.
• W2954284623 cites W2015662894 @default.
• W2954284623 cites W2016151415 @default.
• W2954284623 cites W2018453465 @default.
• W2954284623 cites W2042783871 @default.
• W2954284623 cites W2050912412 @default.
• W2954284623 cites W2052593207 @default.
• W2954284623 cites W2060133690 @default.
• W2954284623 cites W2063963152 @default.
• W2954284623 cites W2074595931 @default.
• W2954284623 cites W2080983287 @default.
• W2954284623 cites W2093255068 @default.
• W2954284623 cites W2093805100 @default.
• W2954284623 cites W2100771939 @default.
• W2954284623 cites W2107277218 @default.
• W2954284623 cites W2109298880 @default.
• W2954284623 cites W2119764013 @default.
• W2954284623 cites W2121354606 @default.
• W2954284623 cites W2143253053 @default.
• W2954284623 cites W2190404250 @default.
• W2954284623 cites W2192080449 @default.
• W2954284623 cites W2513129213 @default.
• W2954284623 cites W2516129687 @default.
• W2954284623 cites W2566408036 @default.
• W2954284623 cites W2604553302 @default.
• W2954284623 cites W2617145180 @default.
• W2954284623 cites W2726089367 @default.
• W2954284623 cites W2750087623 @default.
• W2954284623 cites W2766306821 @default.
• W2954284623 cites W2771328536 @default.
• W2954284623 cites W2789263143 @default.
• W2954284623 cites W2791419854 @default.
• W2954284623 cites W2807776100 @default.
• W2954284623 cites W2954284623 @default.
• W2954284623 doi "https://doi.org/10.1111/bph.14789" @default.
• W2954284623 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6780992" @default.
• W2954284623 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31273753" @default.
• W2954284623 hasPublicationYear "2019" @default.
• W2954284623 type Work @default.
• W2954284623 sameAs 2954284623 @default.
• W2954284623 citedByCount "28" @default.
• W2954284623 countsByYear W29542846232019 @default.
• W2954284623 countsByYear W29542846232020 @default.
• W2954284623 countsByYear W29542846232021 @default.
• W2954284623 countsByYear W29542846232022 @default.
• W2954284623 countsByYear W29542846232023 @default.
• W2954284623 crossrefType "journal-article" @default.
• W2954284623 hasAuthorship W2954284623A5002913273 @default.
• W2954284623 hasAuthorship W2954284623A5019482739 @default.
• W2954284623 hasAuthorship W2954284623A5022491794 @default.
• W2954284623 hasAuthorship W2954284623A5023686004 @default.
• W2954284623 hasAuthorship W2954284623A5025729175 @default.
• W2954284623 hasAuthorship W2954284623A5029115319 @default.
• W2954284623 hasAuthorship W2954284623A5039409144 @default.
• W2954284623 hasAuthorship W2954284623A5048687448 @default.
• W2954284623 hasAuthorship W2954284623A5068675942 @default.
• W2954284623 hasAuthorship W2954284623A5078466007 @default.
• W2954284623 hasAuthorship W2954284623A5090359406 @default.
• W2954284623 hasBestOaLocation W29542846231 @default.
• W2954284623 hasConcept C104317684 @default.
• W2954284623 hasConcept C145059251 @default.
• W2954284623 hasConcept C1491633281 @default.
• W2954284623 hasConcept C150903083 @default.
• W2954284623 hasConcept C185350488 @default.
• W2954284623 hasConcept C185592680 @default.
• W2954284623 hasConcept C20518536 @default.
• W2954284623 hasConcept C207001950 @default.
• W2954284623 hasConcept C28005876 @default.
• W2954284623 hasConcept C28406088 @default.
• W2954284623 hasConcept C2908689518 @default.
• W2954284623 hasConcept C55493867 @default.
• W2954284623 hasConcept C86803240 @default.
• W2954284623 hasConcept C98274493 @default.
• W2954284623 hasConceptScore W2954284623C104317684 @default.
• W2954284623 hasConceptScore W2954284623C145059251 @default.
• W2954284623 hasConceptScore W2954284623C1491633281 @default.
• W2954284623 hasConceptScore W2954284623C150903083 @default.

• next