Optimization of the Urea Linker of Triazolopyridazine MMV665917 Results in a New Anticryptosporidial Lead with Improved Potency and Predicted hERG Safety Margin.
Optimization of the Urea Linker of Triazolopyridazine MMV665917 Results in a New Anticryptosporidial Lead with Improved Potency and Predicted hERG Safety Margin.
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DOI：
10.1021/acs.jmedchem.1c01136
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发表时间：
2021-08-12
影响因子：
7.3
通讯作者：
Meyers MJ
中科院分区：
文献类型：
--
作者：
Oboh E;Schubert TJ;Teixeira JE;Stebbins EE;Miller P;Philo E;Thakellapalli H;Campbell SD;Griggs DW;Huston CD;Meyers MJ
隐孢子虫病是由隐孢子虫寄生虫感染小肠引起的，导致严重腹泻、脱水、吸收不良和潜在死亡。FDA批准的唯一治疗方法对幼儿仅部分有效，对免疫功能低下的患者无效。三唑吡啶MMV 665917是先前报告的具有体内疗效的抗隐孢子虫筛选药物，但对hERG离子通道具有中度抑制作用，这可能预示着心脏毒性。在这里，我们描述了我们的初步发展的构效关系，这种新的铅系列，特别注重优化的哌嗪-脲接头。我们发现，哌嗪-乙酰胺是一种上级连接体，导致SLU-2633的EC 50为0.17 μM，相对于hERG的投影边界改善，小肠中的药代动力学暴露时间延长，体内口服有效，全身暴露量最小。SLU-2633代表了一个重大的进步，朝着确定一个新的有效和安全的治疗隐孢子虫病。
Cryptosporidiosis is caused by infection of the small intestine by Cryptosporidium parasites, resulting in severe diarrhea, dehydration, malabsorption and potentially death. The only FDA-approved therapeutic is only partially effective in young children and ineffective for immunocompromised patients. Triazolopyridine MMV665917 is a previously reported anti-Cryptosporidium screening hit with in vivo efficacy but suffers from modest inhibition of the hERG ion channel which could portend cardiotoxicity. Herein, we describe our initial development of structure-activity relationships of this novel lead series with a particular focus on optimization of the piperazine-urea linker. We have discovered that piperazine-acetamide is a superior linker resulting in identification of SLU-2633 which has an EC50 of 0.17 μM, an improved projected margin versus hERG, a prolonged pharmacokinetic exposure in small intestine, and oral efficacy in vivo with minimal systemic exposure. SLU-2633 represents a significant advancement towards the identification of a new effective and safe treatment for cryptosporidiosis.
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影响因子：
168.9
作者：
Kotloff, Karen L.;Nataro, James P.;Levine, Myron M.
通讯作者：
Levine, Myron M.
5岁以下儿童的腹泻感染与腹泻有关的发病率，死亡率和长期后果：一项荟萃分析研究。
DOI：
10.1016/s2214-109x(18)30283-3
发表时间：
2018-07
期刊：
The Lancet. Global health
影响因子：
--
作者：
Khalil IA;Troeger C;Rao PC;Blacker BF;Brown A;Brewer TG;Colombara DV;De Hostos EL;Engmann C;Guerrant RL;Haque R;Houpt ER;Kang G;Korpe PS;Kotloff KL;Lima AAM;Petri WA Jr;Platts-Mills JA;Shoultz DA;Forouzanfar MH;Hay SI;Reiner RC Jr;Mokdad AH
通讯作者：
Mokdad AH
影响因子：
3.8
作者：
Jin, Byung-Ju;Thiagarajah, Jay R.;Verkman, A. S.
通讯作者：
Verkman, A. S.
DOI：
10.1016/s0140-6736(16)31529-x
发表时间：
2016-09-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Liu J;Platts-Mills JA;Juma J;Kabir F;Nkeze J;Okoi C;Operario DJ;Uddin J;Ahmed S;Alonso PL;Antonio M;Becker SM;Blackwelder WC;Breiman RF;Faruque AS;Fields B;Gratz J;Haque R;Hossain A;Hossain MJ;Jarju S;Qamar F;Iqbal NT;Kwambana B;Mandomando I;McMurry TL;Ochieng C;Ochieng JB;Ochieng M;Onyango C;Panchalingam S;Kalam A;Aziz F;Qureshi S;Ramamurthy T;Roberts JH;Saha D;Sow SO;Stroup SE;Sur D;Tamboura B;Taniuchi M;Tennant SM;Toema D;Wu Y;Zaidi A;Nataro JP;Kotloff KL;Levine MM;Houpt ER
通讯作者：
Houpt ER
影响因子：
6.4
作者：
Arnold, Samuel L. M.;Choi, Ryan;Van Voorhis, Wesley C.
通讯作者：
Van Voorhis, Wesley C.