Emixustat(ACU-4429) is a first in class small-molecule visual cycle modulator that inhibits the isomerase complex. As an inhibitor of visual cycle isomerase, the IC50 value is 4.4 nM[1].
Emixustat strongly inhibits 11-cis-retinol production with an IC50 value of 232±3 nM[2]. A concentration-dependent reduction of 11-cis-ROL production (i.e., inhibition of RPE65 isomerase activity) by emixustat(10-5 to 10-10 M)[1].
Emixustat(0.01-3.0 mg/kg; p.o) was found to reduce the production of visual chromophore (11-cis retinal) in wild-type mice following a single oral dose (ED50 = 0.18 mg/kg) [1]. In 40 subjects (mean age, 38 years) Emixustat (n = 30) (5, 10, 20, 30, or 40 mg; 14-day) was rapidly absorbed (median T(max), 3.0-5 hours) and readily eliminated (mean t(1/2), 4.6-7.9 hours), and mean C(max) generally increased in proportion to dose. Systemic adverse events were minimal[3]. Emixustat significantly abates permeability after Ischemia Reperfusion(IR) on vascular permeability in mice[4].
References:
[1]. Bavik C, Henry SH, et,al.Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity. PLoS One. 2015 May 13;10(5):e0124940. doi: 10.1371/journal.pone.0124940. PMID: 25970164; PMCID: PMC4430241.
[2]. Kiser PD, Zhang J, et,al.Catalytic mechanism of a retinoid isomerase essential for vertebrate vision. Nat Chem Biol. 2015 Jun;11(6):409-15. doi: 10.1038/nchembio.1799. Epub 2015 Apr 20. PMID: 25894083; PMCID: PMC4433804.
[3].Kubota R, Al-Fayoumi S, et,al. Phase 1, dose-ranging study of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in healthy volunteers. Retina. 2014 Mar;34(3):603-9. doi: 10.1097/01.iae.0000434565.80060.f8. PMID: 24056528.
[4].Dreffs A, Lin CM, et,al. All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion. Invest Ophthalmol Vis Sci. 2020 Jun 3;61(6):8. doi: 10.1167/iovs.61.6.8. PMID: 32492112; PMCID: PMC7415894.
Emixustat(ACU-4429)是一种抑制异构酶复合物的小分子视觉周期调节剂。作为视循环异构酶抑制剂,IC50值为4.4 nM[1]。
Emixustat抑制11-顺式视黄醇的产生,IC50值为232±3 nM[2]。Emixustat (10-5 ~ 10-10 M) 以浓度依赖性降低11-cis-ROL的产量 (即抑制RPE65异构酶活性) [1]。
研究发现,单次口服Emixustat (0.01-3.0 mg/kg; p.o)可减少野生型小鼠视觉发色团(11-cis retinal)的产生(ED50 = 0.18 mg/kg)[1]。40名受试者(平均年龄38岁)。Emixustat (n = 30)(5-40 mg;14days)吸收迅速(中位值3.0-5小时),容易消除(平均时间4.6-7.9小时),平均峰浓度随剂量成比例增加。不良事件极少[3]。Emixustat显著降低小鼠缺血再灌注后血管通透性[4]。