Products Cited in Publications Worldwide Neutral sphingomyelinase 2 inhibitors based on the pyrazolo[1,5-a] scaffold

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

Novotna, Katerina; Thomas, Ajit G.; Stepanek, Ondrej; Murphy, Brennan; Hin, Niyada; Skacel, Jan; Mueller, Louis; Tenora, Lukas; Pal, Arindom; Alt, Jesse; Wu, Ying; Paule, James; Rais, Rana; Slusher, Barbara S.; Tsukamoto, Takashi

DOI: PMID:

Abstract

Neutral sphingomyelinase 2 (nSMase2) has gained increasing attention as a therapeutic target to regulate ceramide production in various disease conditions. Ph (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 pharmacol. 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 mols. 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 was found to be metabolically stable in liver microsomes and orally available with a favorable brain-to-plasma ratio, demonstrating the potential of the pyrazolo[1,5-a]pyrimidine ring as an effective scaffold for nSMase2 inhibition.

Keywords

Phosphodiesterase ; Neutral sphingomyelinase 2 ; Sphingomyelin ; Ceramide ; Pyrazolo[1,5-a]pyrimidin-3-amine

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A240931232600-93-097%

3-Aminopyrazolo[1,5-a]pyrimidine

469.0/5g

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