Imidazolopiperazines: lead optimization of the second-generation antimalarial agents.
Imidazolopiperazines: lead optimization of the second-generation antimalarial agents.
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DOI：
10.1021/jm300041e
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发表时间：
2012-05-10
影响因子：
7.3
通讯作者：
Chatterjee, Arnab K.
中科院分区：
文献类型：
--
作者：
Nagle, Advait;Wu, Tao;Kuhen, Kelli;Gagaring, Kerstin;Borboa, Rachel;Francek, Caroline;Chen, Zhong;Plouffe, David;Lin, Xuena;Caldwell, Christopher;Ek, Jared;Skolnik, Suzanne;Liu, Fenghua;Wang, Jianling;Chang, Jonathan;Li, Chun;Liu, Bo;Hollenbeck, Thomas;Tuntland, Tove;Isbell, John;Chuan, Tiffany;Alper, Philip B.;Fischli, Christoph;Brun, Reto;Lakshminarayana, Suresh B.;Rottmann, Matthias;Diagana, Thierry T.;Winzeler, Elizabeth A.;Glynne, Richard;Tully, David C.;Chatterjee, Arnab K.
在优化一系列新型咪唑并哌嗪类化合物的基础上，合成了第二代哌嗪环结构发生变化的化合物，以提高抗疟性能。通过利用一组体外代谢鉴别研究的结果，进行这些变更以进一步改善化合物的效价和代谢稳定性。优化的8，8-二甲基咪唑哌嗪类似物表现出改善的效力、体外代谢稳定性特征，并且因此增强了小鼠体内的口服暴露。在疟疾小鼠模型中，发现优化的化合物比目前的抗疟药更有效。在大鼠药代动力学研究中，它们表现出中度经口暴露，以达到毒理学研究中有效剂量下经口暴露的足够倍数。
On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.
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DOI：
10.1126/science.1193225
发表时间：
2010-09-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Rottmann M;McNamara C;Yeung BK;Lee MC;Zou B;Russell B;Seitz P;Plouffe DM;Dharia NV;Tan J;Cohen SB;Spencer KR;González-Páez GE;Lakshminarayana SB;Goh A;Suwanarusk R;Jegla T;Schmitt EK;Beck HP;Brun R;Nosten F;Renia L;Dartois V;Keller TH;Fidock DA;Winzeler EA;Diagana TT
通讯作者：
Diagana TT
DOI：
10.1007/bf03190489
发表时间：
2003-07-01
影响因子：
1.9
作者：
Yan, Z;Caldwell, GW
通讯作者：
Caldwell, GW
DOI：
10.1073/pnas.0802982105
发表时间：
2008-07-01
影响因子：
11.1
作者：
Plouffe, David;Brinker, Achim;Winzeler, Elizabeth A.
通讯作者：
Winzeler, Elizabeth A.
影响因子：
--
作者：
Dubin, AE;Nasser, N;Mathes, C
通讯作者：
Mathes, C
影响因子：
7.3
作者：
Yeung BK;Zou B;Rottmann M;Lakshminarayana SB;Ang SH;Leong SY;Tan J;Wong J;Keller-Maerki S;Fischli C;Goh A;Schmitt EK;Krastel P;Francotte E;Kuhen K;Plouffe D;Henson K;Wagner T;Winzeler EA;Petersen F;Brun R;Dartois V;Diagana TT;Keller TH
通讯作者：
Keller TH