Novel Functionalyzed 5-Aryl-2-furfuril-N-acylhydrazone Derivatives ...

CONFIDENTIAL
Among these new N-acylhydrazone derivatives the compounds LASSBio-1609 and
LASSBio-1636, can be identified as authentic analgesic prototypes, as both showed improved
antinociceptive activity profile in animal models of inflammatory and neuropathic pain. These
derivatives were capable of decreasing the hipernociception induced by carrageenan and CFA in
mice at 30 and 100 µM concentration, showing a profile very similar to those showed by prototype
A-803467. Also, oral administration of compounds LASSBio-1609 and LASSBio-1636 produced
anti-allodynic and anti-hyperalgesic effects in rats in the Chung model (L5/L6 Spinal Nerve
Ligation - SNL) of neuropathic pain. These effects were comparable to those of the prototype A-
803467 in the same model (Figure 2). In addition, these derivatives proved to have high stability in
rat plasma, featuring, at least partially, an adequate bioavailability profile.
Figure 2: Antinociceptive effect of LASSBio-1609, LASSBio-1636 and A-803467 in SNL
neurophatic pain model in rats. (A) Thermic hypersensibility; (B) Mechanical allodynia.
The novel NAH derivatives LASSBio-1609 and LASSBio1636 did not affected the motor
coordination of mice as observed in the rota-rod test. Additionally, it is important to highlight that
the compounds only interfered with the threshold of nociception in the mice where inflammation
was induced, bringing it back to normal. However, in control mice, the compounds did not affected
the normal threshold for activation of pain. These results demonstrate that these prototypes act only
in the disease level, not affecting the normal physiological functions.
In an attempt to identify the specific molecular mechanism of action of LASSBio-1609 and
LASSBio-1636, electrophysiological (whole-cell patch-clamp technique) in vitro assay was
employed. As a source of NaV1.8 currents (the primary target of NAH derivatives) dorsal root
ganglion cultured neurons were used. To ensure that the NAH compounds are probably acting on
Nav1.8 TTX-R currents, TTX (100 nM) were added to the perfusion solution. It was observed that
even in the presence of TTX, there is a remaining current that is probably composed of Nav1.8 plus
Nav 1.9. The perfusion of cell with LASSBio-1636 (10 µM) reduced TTX-resistant currents. It is
noteworthy that the effect of LASSBio-1636 was washed out suggesting a surmountable effect. This
preliminary result is in line with the hypothesis that LASSBio-1636 is probably a Nav1.8 selective
blocker.
References:
- Kim, Sh; Chung, Jm (1992) An experimental model for peripheral neuropathy produced by
segmental spinal nerve ligation in the rat. Pain 50: 355-363.
- Kort, M. E. et al. (2008) Discovery and biological evaluation of 5-aryl-2-furfuramides, potent
and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and
inflammatory pain. J. Med. Chem. 51: 407-416.
- Rogers M. et al. (2006) The role of sodium channels in neuropathic pain. Semin. Cell. Dev. Biol.
17:571-581.