Pharmacokinetics and Effect of Novel Sydnonimine on NO and cGMP Accumulation In Vivo

Background: Sydnonimines are mesoionic heterocyclic NO donors with vasodilatory activity. Molsidomine, a clinically approved sydnonimine, has limited blood–brain barrier (BBB) penetration, restricting its use for cerebrovascular disorders. This study characterizes the lead compound BBP2023 as a potential NO donor with putative cerebral action. Methods: In silico ADME profiling (RDKit) of 14 sydnonimines, rat pharmacokinetics of oral BBP2023 (11 mg/kg) vs. molsidomine (10.4 mg/kg), HPLC-MS/MS of NO/cGMP, and docking against four human sGC PDB entries were performed. Results: BBP2023 showed high lipophilicity (logP 1.58), low TPSA (69.78 Å2) and predicted high BBB permeability. After oral dosing, BBP2023 was rapidly absorbed (plasma Tmax 0.17 h, Cmax 389 ng/mL, AUC_last 235 h·ng/mL) and extensively distributed, with highest exposure in liver (AUC_last 1457 h·ng/mL, ~6-fold plasma), indicating primary hepatic metabolism. Brain penetration was confirmed (fr = 1.39, MRT 3.01 h). The active metabolite BBP2023 A appeared later (plasma Tmax 1.00 h, Cmax 22 ng/mL) and accumulated in the lungs (fr = 25.31, AUC_last 1569 h·ng/mL) and brain (fr = 3.65, MRT 4.16 h). Compared with molsidomine, BBP2023 achieved higher brain exposure (availability 1.4 vs. 0.2, Cmax 852.5 vs. 142.3 pmol/mL) and faster brain Tmax (≤0.25 h vs. 1 h). BBP2023 significantly increased NO and cGMP in the brain (131.00 ± 26.39 nM/g and 1070.83 ± 92.04 pM/g, respectively), whereas molsidomine predominantly elevated heart NO. Docking and MM-GBSA calculations suggested possible interactions of BBP2023 and its metabolites with the sGC stimulator site and associated the intact sydnonimine ring with more favorable calculated scores. Conclusions: BBP2023 acts as a NO donor with favorable pharmacokinetics, effective BBB penetration, and brain NO/cGMP accumulation, supporting its further development for cerebrovascular disorders.