Trabajo presentado en el IX EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry, celebrado en Zagreb (Croacia), del 3 al 7 de septiembre de 2023Soluble epoxide hydrolase inhibitors (sEHI) are a new class of non-opioid analgesics, with a representative
compound, EC5026, currently in clinical trials for the management of neuropathic pain [1].
Our group has recently designed, synthesized and pharmacologically evaluated novel series of potent
benzohomoadamantane-based sEHI [2]. Herein, we report further medicinal chemistry around the
abovementioned polycyclic scaffold to improve the potency and, particularly, the DMPK properties of previous
hits. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies,
three candidates were selected for in vivo studies. Two compounds evaluated in a murine model of
capsaicin-induced allodynia displayed potent anti-allodynic effect in a dose-dependent manner. Next, the most
potent compound was evaluated in the cyclophosphamide-induced murine model of cystitis, a well-established
model of visceral pain, presenting robust analgesic efficacy [3]. Finally, considering that chemotherapy-induced
neuropathic pain (CINP), a severe side effect of several anticancer agents, is a largely unmet medical need [4],
our third candidate was evaluated in a murine model of paclitaxel-induced neuropathic pain. CINP was
performed by a daily injection of paclitaxel via i.p. (2 mg/kg), for 5 consecutive days. Mice developed
neuropathic mechanical allodynia, which peaked on day 10 after the first paclitaxel administration ¿time when
the acute effects of sEHI were tested. Subcutaneous administration of this candidate (2.5-5 mg/kg) completely
reversed in a dose dependent manner the sensory hypersensitivity. Additionally, administration of the sEHI (5
mg/kg, s.c.) 30 min before each paclitaxel injection completely prevented the development of neuropathic
allodynia. Collectively, these results suggest interstitial cystitis/pain bladder syndrome and CINP as possible
new indications for sEHI.
Acknowledgements: This work was funded by the Grant PID2020-118127RB-I00 funded by
MCIN/AEI/10.13039/501100011033 and by ¿ERDF A way of making Europe¿ to S.V
