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Institute of Organic Chemistry
and Biochemistry of the CAS

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All publications
A novel and potent brain penetrant inhibitor of extracellular vesicle release
A novel and potent brain penetrant inhibitor of extracellular vesicle release
C. Rojas
Michal Šála
A. G. Thomas
A. D. Chaudhury
S.-W. Yoo
Z. Li
R. P. Dash
R. Rais
N. J. Haughey
Radim Nencka
B. Slusher
British Journal of Pharmacology 176 (19): 3857-3870 (2019).

Background and Purpose: 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.

Experimental Approach: 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

Key Results: 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.

Conclusion and Implications: 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.

Diamond nano-optode for fluorescent measurements of pH and temperature
Helena Raabová
David Chvátil
D. Chvátil
Petr Cígler
Nanoscale 11 (40): 18537-18542 (2019).
The redox‐active site of thioredoxin is directly involved in apoptosis signal‐regulating kinase 1 binding that is modulated by oxidative stress
K. Pšenáková
Rozálie Hexnerová
Pavel Srb
V. Obšilová
Václav Veverka
T. Obšil
FEBS Journal - (-): Early View (2019).
Determination of nucleobase-pairing free energies from rotamer equilibria of 2-(methylamino)pyrimidines
Jakub Štoček
Kateřina Bártová
Lucie Čechová
Michal Šála
Ondřej Socha
Zlatko Janeba
Martin Dračínský
Chemical Communications 55 (74): 11075-11078 (2019).

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