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

被引：2

作者：

Novotna, Katerina ^{[1
,4
,5
]}

Thomas, Ajit G. ^{[1
]}

Stepanek, Ondrej ^{[1
,2
]}

Murphy, Brennan ^{[1
,2
]}

Hin, Niyada ^{[1
]}

Skacel, Jan ^{[1
]}

Mueller, Louis ^{[1
,2
]}

Tenora, Lukas ^{[1
,4
]}

Pal, Arindom ^{[1
,2
]}

Alt, Jesse ^{[1
]}

Wu, Ying ^{[1
]}

Paule, James ^{[1
]}

Rais, Rana ^{[1
,2
,3
]}

Slusher, Barbara S. ^{[1
,2
,3
]}

Tsukamoto, Takashi ^{[1
,2
,3
]}

机构：

[1] Johns Hopkins Drug Discovery, Baltimore, MD 21205 USA

[2] Dept Neurol, Baltimore, MD USA

[3] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[4] Acad Sci Czech Republ Vv i, Inst Organ Chem & Biochem, Prague 16600, Czech Republic

[5] Charles Univ Prague, Dept Organ Chem, Prague 12800, Czech Republic

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 259卷

关键词：

Phosphodiesterase; Neutral sphingomyelinase 2; Sphingomyelin; Ceramide; Pyrazolo[1; a ]pyrimidin-3-amine;

D O I：

10.1016/j.ejmech.2023.115674

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页数：10