URB937 is an orally active, peripherally restricted, selective inhibitor of fatty acid amide hydrolase (FAAH) with an IC50 of 26.8nM[1]. FAAH is a membrane-bound serine hydrolase that degrades endocannabinoids such as anandamide and terminate their signal transduction[2]. URB937 regulates the endogenous cannabinoid system by selectively inhibiting peripheral FAAH activity, exerting analgesic and anti-inflammatory effects without affecting central FAAH levels[3]. URB937 is usually used in the study of neurological diseases and inflammation/immunology[4].
In vitro, URB937(0-50µM; 72h) reduced 4T1 breast cancer cells viability but did not affect non-tumor HEK293 cells viability with an EC50 of 16.7μM[5].
In vivo, URB937 (1mg/kg; i.v.) reversed the prostaglandin E2-induced bladder overactivity, increased bladder compliance, and abolished the facilitated C-fiber afferent activity in female Sprague-Dawley rats[6]. URB937 (1mg/kg; i.p.; every other day for 25 days) prevented the development of mechanical allodynia and attenuated the upregulation of pain neuropeptide CGRP and pro-inflammatory cytokines in the medulla, cervical spinal cord, and trigeminal ganglion in a rat model of trigeminal neuralgia[7].
References:
[1] Clapper JR, Moreno-Sanz G, Russo R, et al. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci. 2010;13(10):1265-1270.
[2] Petrosino S, Di Marzo V. FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels. Curr Opin Investig Drugs. 2010;11(1):51-62.
[3] O'Hearn S, Diaz P, Wan BA, et al. Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies. Ann Palliat Med. 2017;6(Suppl 2):S209-S214.
[4] Greco R, Demartini C, Zanaboni A, et al. Characterization of the peripheral FAAH inhibitor, URB937, in animal models of acute and chronic migraine. Neurobiol Dis. 2021;147:105157.
[5] Slivicki RA, Xu Z, Mali SS, Hohmann AG. Brain permeant and impermeant inhibitors of fatty-acid amide hydrolase suppress the development and maintenance of paclitaxel-induced neuropathic pain without producing tolerance or physical dependence in vivo and synergize with paclitaxel to reduce tumor cell line viability in vitro. Pharmacol Res. 2019;142:267-282.
[6] Aizawa N, Gandaglia G, Hedlund P, et al. URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E2 -induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats. BJU Int. 2016;117(5):821-828.
[7] Demartini C, Greco R, Zanaboni AM, Francavilla M, Facchetti S, Tassorelli C. URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia. Pharmaceuticals (Basel). 2023;16(11):1626.
URB937是口服有效的、外周限制性的脂肪酸酰胺水解酶（FAAH）特异性抑制剂，IC50为26.8nM[1]。FAAH是一种膜结合丝氨酸水解酶，可降解内源性大麻素，如anandamide，并终止其信号传导[2]。URB937通过选择性抑制外周FAAH活性调节内源性大麻素系统，发挥镇痛和抗炎作用，且不影响中枢FAAH水平[3]。URB937通常用于神经系统疾病和炎症/免疫学研究[4]。
体外实验中，URB937（0-50µM；72小时）降低了4T1乳腺癌细胞的活性，但对非肿瘤HEK293细胞的活性没有影响，其EC50为16.7µM[5]。
体内实验中，URB937（1mg/kg；静脉注射）逆转了前列腺素E2诱导的大鼠膀胱过度活动，增加了膀胱顺应性，并消除了C纤维传入活动的增强[6]。URB937（1mg/kg；腹腔注射；两天一次，共25天）预防了三叉神经痛大鼠模型中机械性痛觉过敏的发展，并减弱了延髓、颈脊髓和三叉神经节中疼痛神经肽CGRP和促炎细胞因子的上调[7]。