Sandra Codony1, Beatrice Jora1, Miriam Santos-Caballero2, Andreea L. Turcu1, Carla Calvó-Tusell3, Christophe Morisseau4, M. Isabel Loza5, José M. Brea5, Clara Bartra6, Coral Sanfeliu6, Belén Pérez7, Christian Griñán-Ferré8, Mercè Pallàs8, Bruce D. Hammock4, Sílvia Osuna3,9, Ferran Feixas3, Enrique J. Cobos2, Santiago Vázquez1.
1Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l’Alimentació i Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain. 2Department of Pharmacology, Faculty of Medicine and Biomedical Research Center (Neurosciences Institute), University of Granada. Biosanitary Research Institute ibs.GRANADA, Avenida de la Investigación 11, 18016, Granada, Spain. 3CompBioLab Group, Departament de Química and Institut de Química Computacional i Catàlisi (IQCC), Universitat de Girona, C/ Maria Aurèlia Capmany 69, 17003 Girona, Spain. 4Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA. 5Innopharma Screening Platform, Biofarma Research Group, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, Universidad de Santiago de Compostela, Edificio CIMUS, Av. Barcelona, S/N, E-15706 Santiago de Compostela, Spain. 6August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. 7Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, E-08193 Bellaterra, Spain. 8Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neurosciences (NeuroUB), Universitat de Barcelona, Av. Joan XXIII 27-31, 08028 Barcelona, Spain. 9Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
Chemotherapy-induced neuropathic pain (CINP) is a severe side effect of several anticancer agents, such as oxaliplatin, cisplatin, carboplatin and paclitaxel. The prevalence of CIPN is high, is the primary dose-limiting factor of several chemotherapy treatments and can last even after stopping the treatment. Although several analgesics are prescribed to treat painful CIPN, they are either ineffective (NSAIDs) or endowed with severe side effects (narcotics, gabapentinoids). Therefore, there are no current therapies that offer adequate relief for CINP [1].
Soluble 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 [2,3]. In the last few years, our group has designed, synthesized and pharmacologically evaluated novel series of potent benzohomoadamantane-based sEHI and we found that a selected compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain [4].
Herein, we report further medicinal chemistry around the abovementioned polycyclic scaffold in order to improve DMPK properties of previous hits. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, a candidate was evaluated in vivo in a murine model of CINP.
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 EC5026 (1.25-5 mg/kg) or UB-BJ-01 (2.5-5 mg/kg) completely reversed in a dose dependent manner the sensory hypersensitivity, and this effect was abolished by the administration of MSPPOH (20 mg/kg, s.c.), indicating the selectivity of their antiallodynic effects. Finally, administration of UB-BJ-01 (5 mg/kg, s.c.) 30 min before each paclitaxel injection completely prevented the development of neuropathic allodynia.
[1] Chemotherapy-induced peripheral neuropathy: part 1-current state of knowledge and perspectives for pharmacotherapy. Pharmacol. Rep. 2020, 72, 486-507.
[2] Movement to the clinic of soluble epoxide hydrolase inhibitor EC5026 as an analgesic for neuropathic pain and for use as a nonaddictive opioid alternative. J. Med. Chem. 2021, 64, 1856−1872.
[3] Soluble epoxide hydrolase inhibition alleviates chemotherapy induced neuropathic pain. Front. Pain Res. 2023, 3, 1100524.
[4] Synthesis, in vitro profiling, and in vivo evaluation of benzohomoadamantane-based ureas for visceral pain: a new indication for soluble epoxide hydrolase inhibitors. J. Med. Chem. 2022, 65, 13660-13680.
