Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target.
Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target.
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DOI：
10.1021/acs.jmedchem.1c01586
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发表时间：
2022-01-13
影响因子：
7.3
通讯作者：
Wyatt PG
中科院分区：
文献类型：
--
作者：
Wilson C;Ray P;Zuccotto F;Hernandez J;Aggarwal A;Mackenzie C;Caldwell N;Taylor M;Huggett M;Mathieson M;Murugesan D;Smith A;Davis S;Cocco M;Parai MK;Acharya A;Tamaki F;Scullion P;Epemolu O;Riley J;Stojanovski L;Lopez-Román EM;Torres-Gómez PA;Toledo AM;Guijarro-Lopez L;Camino I;Engelhart CA;Schnappinger D;Massoudi LM;Lenaerts A;Robertson GT;Walpole C;Matthews D;Floyd D;Sacchettini JC;Read KD;Encinas L;Bates RH;Green SR;Wyatt PG
随着结核病患者耐药性的增加，迫切需要新的药物。理想情况下，新的药物应该通过新的靶点起作用，这样它们就不会受到对当前治疗的预先存在的临床耐药性的阻碍。苯并呋喃1被认为是结核抑制新靶点Pks13的硫酯酶结构域的潜在先导物。虽然具有抗结核分枝杆菌的活性，但其主要作用是抑制hERG心脏离子通道。本文描述了该系列的临床前候选药物的优化。尽管在体外改善了hERG负荷，但在体外心脏毒性模型中评估新化合物时，它们仍然会引起心脏不规则。由于担心安全窗口不足，进一步的系列开发被停止。然而，多个系列成员体内活性的证明进一步验证了Pks13作为抗结核药物的一个有吸引力的新靶点，并支持了替代化学型的开发。
With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.
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影响因子：
--
作者：
Gavalda, Sabine;Bardou, Fabienne;Quemard, Annaik
通讯作者：
Quemard, Annaik
影响因子：
6.4
作者：
DeJesus MA;Gerrick ER;Xu W;Park SW;Long JE;Boutte CC;Rubin EJ;Schnappinger D;Ehrt S;Fortune SM;Sassetti CM;Ioerger TR
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Ioerger TR
影响因子：
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作者：
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Mason, Jonathan S.
影响因子：
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作者：
MIYAURA, N;YAMADA, K;SUZUKI, A
通讯作者：
SUZUKI, A
影响因子：
7.3
作者：
Guardia, Ana;Baiget, Jessica;Alemparte, Carlos
通讯作者：
Alemparte, Carlos