Interaction of SZV 1287, a novel oxime analgesic drug candidate, and its metabolites with serum albumin

Eszter Fliszár-Nyúl,Zelma Faisal,Violetta Mohos,Diána Derdák,Beáta Lemli,Tamás Kálai,Cecília Sár,Balázs Z Zsidó,Csaba Hetényi,Ádám I Horváth,Zsuzsanna Helyes,Ruth Deme,Dóra Bogdán,Andrea Czompa,Péter Mátyus,Miklós Poór

doi:10.1016/j.molliq.2021.115945

Eszter Fliszár-Nyúl, Zelma Faisal + Show 14 more

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https://doi.org/10.1016/j.molliq.2021.115945

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Abstract

SZV 1287 is our novel multi-target analgesic, which seems to be a promising drug candidate for the treatment of neuropathic pain. Therefore, the drug development process has been started in 2016. Since the pharmacokinetic characterization of a drug candidate is essential and albumin binding of drugs can strongly affect their pharmacokinetic properties, herein we provided the detailed investigation and characterization of the interaction of SZV 1287 and its known metabolites with serum albumin. In a preliminary animal study, we demonstrated the appearance of SZV 1287, oxaprozin, L 2799, L 2805, and L 2811 in the circulation after the per os administration of the parent compound to rats. Then albumin-ligand interactions were examined employing fluorescence spectroscopy, affinity chromatography, ultrafiltration, ultracentrifugation, and molecular modeling. Finally, we tested the potential species dependent differences in the albumin binding of SZV 1287, employing human, bovine, porcine, and rat serum albumins. Our results demonstrated that SZV 1287 and its metabolites form highly stable complexes with albumin (Ka = 105 to 106 L/mol). Furthermore, SZV 1287 occupies Sudlow’s Site II on human serum albumin. Therefore, it is reasonable to hypothesize that SZV 1287-albumin interaction is an important issue regarding the pharmacokinetics of this drug candidate.

Highlights

SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime; Fig. 1), our novel multi-targeting analgesic candidate, is currently being developed for the treatment of neuropathic pain [1]
We aimed to investigate the appearance of SZV 1287 and its suspected metabolites in the circulation
The displacement of naproxen from Human serum albumin (HSA) suggests that the high-affinity binding site of SZV 1287 and its metabolites is located in s Site II (SSII)

Summary

Introduction

SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime; Fig. 1), our novel multi-targeting analgesic candidate, is currently being developed for the treatment of neuropathic pain [1]. SZV 1287 is the oxime analog of oxaprozin, a non-steroidal antiinflammatory drug which has been used in the therapy for a long time [2]. ⇑ Corresponding author at: Department of Pharmacology, Faculty of Pharmacy, the metabolism-activated multi-targeting (MAMUT) concept, where the synergistic pharmacological effects of the parent drug and its active metabolite(s) are utilized [3,4]. The parent drug directly blocks amine oxidase copper containing 3 (AOC3), known as vascular adhesion protein-1. An active metabolite of SZV 1287, the cyclooxygenase (COX) inhibitor oxaprozin is formed at acidic pH in the gastric juice or as a result of biotransformation [3].

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