(R)-(+)-Etomoxir sodium salt(Etomoxir) is a small molecule developed for metabolic and cardiovascular disease that exhibits nanomolar potency toward CPT-1a and CPT-1b upon enzymatic conversion to the active inhibitor etomoxiryl CoA (IC50 = 0.01-0.70 µM) [1-3].
Etomoxir (50 µM ETO; every other day in 10days) reduces CD28-costimulated T cell proliferation without affecting T cell effector differentiation[4]. Low concentrations(3µM,24h) of etomoxir effectively inhibit CPT-1 but do not affect M(IL-4) polarization, High concentrations of Etomoxir (200 µM) inhibit M(IL-4) polarization independently of CPT-1 activity in BMDM cells[5]. Besides the effect of etomoxil on T cell differentiation and function was independent of Cpt1a expression [6].
Etomoxir (40 mg/kg;i.p; every other day for 20 days) suppressed human bladder cancer (BCa) cell growth in vivo[7]. Etomoxir (i.p; 1 mg/kg Etomoxir; twice every week) significantly inhibits the decrease of bone mineral density (BMD) and bone breaking strength in db/db and high fat (HF)-fed mice and suppresses the reduction of BMSCs-differentiated osteoblasts [8].
References:
[1]. O'Connor RS, Guo L, et,al.The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations. Sci Rep. 2018 Apr 19;8(1):6289. doi: 10.1038/s41598-018-24676-6. PMID: 29674640; PMCID: PMC5908836.
[2]. Divakaruni AS, Hsieh WY, et,al. Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis. Cell Metab. 2018 Sep 4;28(3):490-503.e7. doi: 10.1016/j.cmet.2018.06.001. Epub 2018 Jun 28. PMID: 30043752; PMCID: PMC6125190.
[3]. Ceccarelli SM, Chomienne O, et,al. Carnitine palmitoyltransferase (CPT) modulators: a medicinal chemistry perspective on 35 years of research. J Med Chem. 2011 May 12;54(9):3109-52. doi: 10.1021/jm100809g. Epub 2011 Apr 19. PMID: 21504156.
[4]. O'Connor RS, Guo L, et,al. The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations. Sci Rep. 2018 Apr 19;8(1):6289. doi: 10.1038/s41598-018-24676-6. PMID: 29674640; PMCID: PMC5908836.
[5]. Divakaruni AS, Hsieh WY, et,al. Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis. Cell Metab. 2018 Sep 4;28(3):490-503.e7. doi: 10.1016/j.cmet.2018.06.001. Epub 2018 Jun 28. PMID: 30043752; PMCID: PMC6125190.
[6]. Raud B, Roy DG, et,al. Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated Fatty Acid Oxidation. Cell Metab. 2018 Sep 4;28(3):504-515.e7. doi: 10.1016/j.cmet.2018.06.002. Epub 2018 Jun 28. PMID: 30043753; PMCID: PMC6747686.
[7]. Cheng S, Wang G, et,al.Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARγ-mediated pathway in bladder cancer. Clin Sci (Lond). 2019 Aug 7;133(15):1745-1758. doi: 10.1042/CS20190587. PMID: 31358595.
[8]. Li J, He W, et,al.FFA-ROS-P53-mediated mitochondrial apoptosis contributes to reduction of osteoblastogenesis and bone mass in type 2 diabetes mellitus. Sci Rep. 2015 Jul 31;5:12724. doi: 10.1038/srep12724. PMID: 26226833; PMCID: PMC4521203.
(R)-(+)-Etomoxir sodium salt(Etomoxir; ETO)是一种用于代谢和心血管疾病的小分子,经酶转化为活性抑制剂乙托莫西里尔辅酶a (IC50 约为0.01-0.70 µM)后,对CPT-1a和CPT-1b的抑制表现出纳摩尔效价[1-3]。
Etomoxir能减少CD28共刺激的T细胞增殖而不影响T细胞效应分化[4]。低浓度(3µM,24h) Etomoxir可有效抑制CPT-1,但不影响M(IL-4)极化,高浓度(200 µM) Etomoxir可抑制BMDM细胞中M(IL-4)极化,而不影响CPT-1活性[5]。Etomoxir对T细胞分化和功能的影响不依赖于Cpt1a的表达[6]。
Etomoxir (40 mg/kg;i.p; every other day for 20 days)体内抑制人膀胱癌(BCa)细胞生长[7]。Etomoxir(i.p; 1 mg/kg Etomoxir; twice every week)抑制db/db和高脂喂养小鼠骨密度(BMD)和骨折强度的下降,抑制BMSCs分化成骨细胞的减少[8]。