Pharmacokinetics and Effect of Novel Sydnonimine on NO and cGMP Accumulation In Vivo
Year: 2026
Type: article
Abstract: 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.
Source: Pharmaceuticals
DOI: 10.3390/ph19111776
Institutions: Tver State Medical University, Ministry of Health of the Russian Federation, Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Russian Academy of Sciences, Pirogov Russian National Research Medical University, Institute of Bioorganic Chemistry
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7225654290