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

0574332 - ÚOCHB 2024 RIV NL eng J - Článek v odborném periodiku
Novotná, Kateřina - Thomas, A. G. - Štěpánek, O. - Murphy, B. - Hin, N. - Skácel, J. - Mueller, L. - Tenora, Lukáš - Pal, A. - Alt, J. - Wu, Y. - Paule, J. - Rais, R. - Slusher, B. S. - Tsukamoto, T.
Neutral sphingomyelinase 2 inhibitors based on the pyrazolo[1,5-a]pyrimidin-3-amine scaffold.
European Journal of Medicinal Chemistry. Roč. 259, November (2023), č. článku 115674. ISSN 0223-5234. E-ISSN 1768-3254
Institucionální podpora: RVO:61388963
Klíčová slova: phosphodiesterase * neutral sphingomyelinase 2 * ceramide * sphingomyelin * pyrazolo[1,5-a]pyrimidin-3-amine
Obor OECD: Medicinal chemistry
Impakt faktor: 6.7, rok: 2022
Způsob publikování: Omezený přístup
https://doi.org/10.1016/j.ejmech.2023.115674

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.
Trvalý link: https://hdl.handle.net/11104/0344672