Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain.

Ádám István Horváth,Péter Mátyus,Tamás Kálai,Zsuzsanna Helyes,Éva Nagyné Scholz,Tamás Mészáros,Eszter Fliszár-Nyúl,Krisztina Percze,Szilárd Pál,Cecília Sár,Valéria Tékus,András Garami,Maja Payrits,Miklós Poór,Éva Szőke,Blanka Tóth,Emőke Oláh,Nikolett Szentes

doi:10.3390/biomedicines9070749

Abstract

SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate.

Highlights

Neuropathic pain of 3–17% prevalence represents a great unmet medical need, since the conventional and adjuvant analgesics are frequently ineffective, and they exert the broad range of severe adverse effects upon long-term use [1,2,3,4]
We have recently shown that, independently of its amine oxidase copper containing 3 (AOC3) inhibitory action, SZV 1287 directly antagonizes the pain-sensing transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) receptors, which are non-selective cation channels on nociceptive primary sensory neurons [10]
The unique feature distinguishing this compound from other AOC3 inhibitors is that it was designed on the basis of a novel, innovative drug design strategy termed as metabolism-activated multitargeting (MAMUT) [8]

Summary

Introduction

Neuropathic pain of 3–17% prevalence represents a great unmet medical need, since the conventional and adjuvant analgesics are frequently ineffective, and they exert the broad range of severe adverse effects upon long-term use [1,2,3,4]. Our novel, multi-target drug candidate SZV 1287 (3-(4,5-diphenyl-1,3oxazol-2-yl) propanal oxime) offers a substantial breakthrough for the treatment of neuropathic pain [5]. SZV 1287 is an oxime analogue of the cyclooxygenase (COX) inhibitor oxaprozin, which has been used for a long time as a classical non-steroidal antiinflammatory drug with the indication of osteoarthritis (OA) and rheumatoid arthritis (RA) [6,7]. SZV 1287 itself is an irreversible amine oxidase copper containing 3 (AOC3) inhibitor, and it is metabolized mainly to the COX inhibitor oxaprozin throughout the body [8]. We have recently shown that, independently of its AOC3 inhibitory action, SZV 1287 directly antagonizes the pain-sensing transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) receptors, which are non-selective cation channels on nociceptive primary sensory neurons [10]

Methods

Results

Conclusion