当前位置: X-MOL 学术ACS Med. Chem. Lett. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Dipeptide Prodrugs of the Glutamate Modulator Riluzole
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2018-06-15 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00189
Jeffrey C. Pelletier 1 , Suzie Chen 2 , Haiyan Bian 1 , Raj Shah 2 , Garry R. Smith 1 , Jay E. Wrobel 1 , Allen B. Reitz 1, 3
Affiliation  

We have previously reported a prodrug strategy based on the marketed drug riluzole (2-amino-6-trifluoromethoxybenzothiazole), associated with the benefits of lower patient to patient variability of exposure and potentially once daily oral dosing, as opposed to the large variance and twice daily dosing, which is currently observed with the parent drug. Riluzole is a glutamate modulator that is currently approved by the US FDA to treat amyotrophic lateral sclerosis (ALS). Riluzole also strongly suppresses the growth of melanoma cells that express the type 1 metabotropic glutamate receptor (GRM1, mGluR1). Riluzole is a substrate for the variably expressed liver isozyme CYP1A2, which has been shown to contribute to the variance in exposure of riluzole in humans upon oral administration. In addition, an elevated Cmax following oral administration is a probable cause of increased liver enzyme levels in some patients. In order to mitigate these issues, a series of natural and unnatural dipeptide prodrugs of riluzole were prepared as products that bear lower first-pass hepatic clearance. The prodrugs were evaluated for their ability to produce riluzole in serum while remaining intact prior to absorption from the GI tract, characteristic of a type IIB prodrug. Here, we describe dipeptide conjugates of riluzole and report that the t-Bu-Gly-Sar-riluzole analog FC-3423 (6) is absorbed well and converts to riluzole in rats and mice in a regular and well-defined manner. FC-3423 strongly suppress tumor cell growth in mouse xenograft models of melanoma at a molar dose 10-fold less than that of riluzole itself.

中文翻译:

谷氨酸调节剂利鲁唑的二肽前药

先前我们已经报道了基于市售药物riluzole(2-氨基-6-三氟甲氧基苯并噻唑)的前药策略,该策略与降低患者对患者的暴露差异性以及每天口服一次可能的益处有关,这与较大的差异和两次每日剂量,目前在母体药物中观察到。利鲁唑是一种谷氨酸调节剂,目前已被美国FDA批准用于治疗肌萎缩性侧索硬化症(ALS)。利鲁唑还强烈抑制表达1型代谢型谷氨酸受体(GRM1,mGluR1)的黑素瘤细胞的生长。利鲁唑是可变表达的肝脏同工酶CYP1A2的底物,已显示其对人体口服利鲁唑的暴露差异有贡献。另外,C升高在某些患者中,口服后max可能是导致肝酶水平升高的原因。为了减轻这些问题,制备了一系列利鲁唑的天然和非天然二肽前药,作为具有较低的首过肝清除率的产品。评价前药在血清中产生利鲁唑的能力,同时在从胃肠道吸收之前保持完整,这是IIB型前药的特征。在这里,我们描述了利鲁唑的二肽缀合物,并报道了t -Bu-Gly-Sar-鲁鲁唑类似物FC-3423(6)吸收良好,并以规则和明确的方式在大鼠和小鼠中转化为利鲁唑。FC-3423在小鼠异种移植黑素瘤模型中以比利鲁唑本身的摩尔剂量低10倍的摩尔剂量强烈抑制肿瘤细胞的生长。
更新日期:2018-06-15
down
wechat
bug