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Neutral sphingomyelinase 2 inhibitors based on the pyrazolo[1,5-a]pyrimidin-3-amine scaffold

. 2023 Nov 05 ; 259 () : 115674. [epub] 20230726

Language English Country France Media print-electronic

Document type Journal Article

Grant support
P30 MH075673 NIMH NIH HHS - United States
R01 AG059799 NIA NIH HHS - United States
T32 AG058527 NIA NIH HHS - United States

Links

PubMed 37536209
PubMed Central PMC10529203
DOI 10.1016/j.ejmech.2023.115674
PII: S0223-5234(23)00640-2
Knihovny.cz E-resources

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.

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