Next-Generation Neutral Sphingomyelinase-2 Inhibitors with Improved Solubility, Pharmacokinetics, and Efficacy in a Tau Propagation Model

Abstract Neutral sphingomyelinase 2 (nSMase2) is a promising therapeutic target implicated in disease progression. We previously identified PDDC [phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)-pyrrolidin-3-yl) carbamate], a sub-micromolar nSMase2 inhibitor with favorable efficacy and pharmacokinetics in mice. However, poor aqueous solubility and suboptimal pharmacokinetics in higher species limited its translational potential. To overcome these limitations, we introduced hydroxy groups on the southern phenyl ring and simultaneously optimized the northern phenyl-carbamate moiety. Compound 8a [(phenyl (R)-(1-(3-(4-hydroxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl) carbamate] exhibited comparable potency and pharmacokinetics to PDDC but remained poorly soluble. To address this, we derivatized the hydroxy group with hydrophilic phosphate promoeities, generating soluble analogues of 8a. Of these, 12a demonstrated excellent aqueous solubility and efficiently released 8a, resulting in improved pharmacokinetics, target engagement, and efficacy in mice. In dogs, oral dosing of 12a resulted in the release of 8a, with the released 8a exhibiting 47% absolute oral bioavailability, supporting its translational potential.