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

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

  • Eur J Med Chem. 2023 Nov 5;259:115674. doi: 10.1016/j.ejmech.2023.115674.
Katerina Novotna 1,  Ajit G Thomas 2,  Ondrej Stepanek 3,  Brennan Murphy 3,  Niyada Hin 2,  Jan Skacel 2,  Louis Mueller 3,  Lukas Tenora 4,  Arindom Pal 3,  Jesse Alt 2,  Ying Wu 2,  James Paule 2,  Rana Rais 5,  Barbara S Slusher 5,  Takashi Tsukamoto 6
Affiliations

Affiliations

  • 1 Johns Hopkins Drug Discovery, United States; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic V.v.i., Prague, 166 00, Czech Republic; Department of Organic Chemistry, Charles University, Prague, 128 00, Czech Republic.
  • 2 Johns Hopkins Drug Discovery, United States.
  • 3 Johns Hopkins Drug Discovery, United States; Department of Neurology, United States.
  • 4 Johns Hopkins Drug Discovery, United States; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic V.v.i., Prague, 166 00, Czech Republic.
  • 5 Johns Hopkins Drug Discovery, United States; Department of Neurology, United States; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, United States.
  • 6 Johns Hopkins Drug Discovery, United States; Department of Neurology, United States; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, United States. Electronic address: ttsukamoto@jhmi.edu.
PMID: 37536209 DOI: 10.1016/j.ejmech.2023.115674
Abstract

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.

Keywords

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

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