title: Stability and hydrolysis kinetics of spirosuccinimide type inhibitors of aldose reductase in aqueous solution and retardation of their hydrolysis by the target enzyme.
abstract: The stability and the hydrolysis kinetics of spirosuccinimide type aldose reductase (AR) inhibitors, SX-3030 (racemate) and its optical enantiomers (R- and S-isomers), were investigated in aqueous solution. The hydrolysis followed pseudo-first-order kinetics and showed significant pH dependence. Maximum solution stability was observed below pH 2.4, whereas the hydrolysis was gradually catalyzed by hydroxide ion at neutral to alkaline pH while the compounds exhibiting moderate pH-independent stability at acidic to neutral conditions (pH 4-7) to enable oral administration. A pK of 3.7 was obtained from the pH-rate profile, but this kinetically derived pK is approximately 2 pH units below the pK of the parent compounds, suggesting the presence of an acidic intermediate involved in the hydrolysis process. These findings, together with structural analysis, support the notion that the hydrolysis would proceed via nucleophilic attack of a water molecule or hydroxide ion on the scissile carbonyl bond of the succinimide ring to form a succinamic acid intermediate that has a beta-keto acid structure, followed by decarboxylation to give a racemized succinimide ring-opened product. On the other hand, the interconversion of the R- and S-isomers did not occur during hydrolysis; however, the hydrolysis of the R-isomer was markedly suppressed by the target enzyme AR whereas that of the S-isomer was not, indicating a high degree of complementarity of interacting surfaces between the R-isomer and the enzyme. The results in the present study could provide useful clues for facilitating the appropriate stabilization strategies as well as for evaluating the pharmacological effects on target tissues in vivo, and suggested that the R-isomer may be a suitable candidate as AR inhibitor.
authors.affiliation: Chemistry Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Enoki 33-94, Suita, Osaka 564-0053, Japan. masuo-kurono@ds-pharma.co.jp
authors.forename: Masuo
authors.initials: M
authors.lastname: Kurono
authors.forename: Akira
authors.initials: A
authors.lastname: Itogawa
authors.forename: Hideto
authors.initials: H
authors.lastname: Noguchi
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Sanjoba
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D048909:Diabetes Complications / Q000188:drug therapy; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D009994:Osmolar Concentration; D011719:Pyrazines / Q000737:chemistry* / Q000627:therapeutic use; D012996:Solutions; D013141:Spiro Compounds / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D011719:Pyrazines; D012996:Solutions; D013141:Spiro Compounds; D000449:Aldehyde Reductase; C115070:ranirestat