Neutral sphingomyelinase 2 (nSMase2) has gained increasing attention as a therapeutic target to regulate ceramide production in various disease conditions. Phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)-pyrrolidin-3-yl)carbamate (PDDC) is a submicromolar nSMase2 inhibitor and has been widely used to study the pharmacological effects of nSMase2 inhibition. Through screening of compounds containing a bicyclic 5-6 fused ring, larotrectinib containing a pyrazolo[1,5-a]pyrimidine ring was identified as a low micromolar inhibitor of nSMase2. This prompted us to investigate the pyrazolo[1,5-a]pyrimidin-3-amine ring as a novel scaffold to replace the imidazo[1,2-b]pyridazine-8-amine ring of PDDC. A series of molecules containing a pyrazolo[1,5-a]pyrimidin-3-amine ring were synthesized and tested for their ability to inhibit human nSMase2. Several compounds exhibited nSMase2 inhibitory potency superior to that of PDDC. Among these, N,N-dimethyl-5-morpholinopyrazolo[1,5-a]pyrimidin-3-amine (11j) was found to be metabolically stable in liver microsomes and orally available with a favorable brain-to-plasma ratio, demonstrating the potential of pyrazolo[1,5-a]pyrimidine ring as an effective scaffold for nSMase2 inhibition.

• Klíčová slova
• Ceramide, Neutral sphingomyelinase 2, Phosphodiesterase, Pyrazolo[1,5-a]pyrimidin-3-amine, Sphingomyelin,
• MeSH
• aminy * MeSH
• ceramidy MeSH
• lidé MeSH
• pyrimidiny farmakologie   MeSH
• sfingomyelinfosfodiesterasa * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aminy * MeSH
• ceramidy MeSH
• pyrenedodecanoylcarnitine MeSH Prohlížeč
• pyrimidiny MeSH
• sfingomyelinfosfodiesterasa * MeSH

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.

• MeSH
• Alzheimerova nemoc farmakoterapie   patologie   MeSH
• exozómy metabolismus   MeSH
• inhibitory enzymů chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mozek metabolismus   MeSH
• myši transgenní MeSH
• myši MeSH
• pyridaziny chemie   metabolismus   terapeutické užití   MeSH
• sfingomyelinfosfodiesterasa antagonisté a inhibitory   metabolismus   farmakologie   MeSH
• tělesná hmotnost účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory enzymů MeSH
• pyridaziny MeSH
• sfingomyelinfosfodiesterasa MeSH
• SMPD3 protein, human MeSH Prohlížeč