当前位置：
X-MOL 学术
›
ACS Infect. Dis.
›
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.)
Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-09-27 00:00:00 , DOI: 10.1021/acsinfecdis.7b00062 Lisa Frueh 1, 2 , Yuexin Li 1 , Michael W Mather 3 , Qigui Li 4 , Sovitj Pou 2 , Aaron Nilsen 1 , Rolf W Winter 1 , Isaac P Forquer 1 , April M Pershing 3 , Lisa H Xie 4 , Martin J Smilkstein 1 , Diana Caridha 4 , Dennis R Koop 5 , Robert F Campbell 4 , Richard J Sciotti 4 , Mara Kreishman-Deitrick 4 , Jane X Kelly 1 , Brian Vesely 4 , Akhil B Vaidya 3 , Michael K Riscoe 1
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-09-27 00:00:00 , DOI: 10.1021/acsinfecdis.7b00062 Lisa Frueh 1, 2 , Yuexin Li 1 , Michael W Mather 3 , Qigui Li 4 , Sovitj Pou 2 , Aaron Nilsen 1 , Rolf W Winter 1 , Isaac P Forquer 1 , April M Pershing 3 , Lisa H Xie 4 , Martin J Smilkstein 1 , Diana Caridha 4 , Dennis R Koop 5 , Robert F Campbell 4 , Richard J Sciotti 4 , Mara Kreishman-Deitrick 4 , Jane X Kelly 1 , Brian Vesely 4 , Akhil B Vaidya 3 , Michael K Riscoe 1
Affiliation
|
ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. While ELQ-300 is highly effective when administered in a low multidose regimen, poor aqueous solubility and high crystallinity have hindered its clinical development. To overcome its challenging physiochemical properties, a number of bioreversible alkoxycarbonate ester prodrugs of ELQ-300 were synthesized. These bioreversible prodrugs are converted to ELQ-300 by host and parasite esterase action in the liver and bloodstream of the host. One such alkoxycarbonate prodrug, ELQ-331, is curative against Plasmodium yoelii with a single low dose of 3 mg/kg in a murine model of patent malaria infection. ELQ-331 is at least as fully protective as ELQ-300 in a murine malaria prophylaxis model when delivered 24 h before sporozoite inoculation at an oral dose of 1 mg/kg. Here, we show that ELQ-331 is a promising prodrug of ELQ-300 with improved physiochemical and metabolic properties and excellent potential for clinical formulation.
中文翻译：
临床前候选药物ELQ-300的烷氧基碳酸酯前药用于预防和治疗疟疾。
ELQ-300是一种临床前抗疟药物，对恶性疟原虫的肝脏，血液和传播阶段具有活性。虽然ELQ-300在低剂量的多剂量方案中非常有效，但水溶性差和结晶度高却阻碍了其临床发展。为了克服其具有挑战性的理化性质，合成了许多ELQ-300的生物可逆烷氧基碳酸酯前药。这些生物可逆性前药通过宿主和宿主肝脏和血流中的寄生虫酯酶作用转化为ELQ-300。一种这样的烷氧基碳酸酯前药ELQ-331可治愈约氏疟原虫在专利性疟疾感染的鼠模型中以3 mg / kg的单次低剂量服用。在小鼠疟疾预防模型中，在子孢子接种前24小时以1 mg / kg的口服剂量给药时，ELQ-331至少具有与ELQ-300完全相同的保护作用。在这里，我们证明ELQ-331是ELQ-300的有前途的前药，具有改善的理化和代谢特性以及极好的临床配方潜力。
更新日期：2017-09-27
中文翻译：
临床前候选药物ELQ-300的烷氧基碳酸酯前药用于预防和治疗疟疾。
ELQ-300是一种临床前抗疟药物，对恶性疟原虫的肝脏，血液和传播阶段具有活性。虽然ELQ-300在低剂量的多剂量方案中非常有效，但水溶性差和结晶度高却阻碍了其临床发展。为了克服其具有挑战性的理化性质，合成了许多ELQ-300的生物可逆烷氧基碳酸酯前药。这些生物可逆性前药通过宿主和宿主肝脏和血流中的寄生虫酯酶作用转化为ELQ-300。一种这样的烷氧基碳酸酯前药ELQ-331可治愈约氏疟原虫在专利性疟疾感染的鼠模型中以3 mg / kg的单次低剂量服用。在小鼠疟疾预防模型中，在子孢子接种前24小时以1 mg / kg的口服剂量给药时，ELQ-331至少具有与ELQ-300完全相同的保护作用。在这里，我们证明ELQ-331是ELQ-300的有前途的前药，具有改善的理化和代谢特性以及极好的临床配方潜力。
京公网安备 11010802027423号