Neutral sphingomyelinase 2 inhibitors based on the imidazo[1,2-b]pyridazin-3-amine scaffold

Neutral sphingomyelinase 2 (nSMase2) catalyzes the hydrolysis of sphingomyelin to generate ceramide and phosphocholine and has emerged as a potential therapeutic target for diseases associated with dysregulated ceramide signaling. Phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate (PDDC), a submicromolar nSMase2 inhibitor based on an imidazo[1,2-b]pyridazin-8-amine scaffold, has been widely used to investigate the pharmacological effects of nSMase2 inhibition. In the course of our efforts to expand the structural diversity of nSMase2 inhibitors, we identified the imidazo[1,2-b]pyridazin-3-amine scaffold as a novel chemotype for nSMase2 inhibition. Systematic structure-activity relationship studies led to several submicromolar nSMase2 inhibitors, although the series generally exhibited high clearance in liver microsomes. These studies establish the imidazo[1,2-b]pyridazin-3-amine scaffold as a promising framework for the development of potent nSMase2 inhibitors while highlighting metabolic stability as a key remaining challenge for this chemotype.