Aminothiazoles: Hit to lead development to identify antileishmanial agents
Aminothiazoles: Hit to lead development to identify antileishmanial agents
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DOI：
10.1016/j.ejmech.2015.08.013
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发表时间：
2015-09-18
影响因子：
6.7
通讯作者：
Martin, Denis
中科院分区：
文献类型：
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作者：
Bhuniya, Debnath;Mukkavilli, Rao;Martin, Denis
作为被忽视疾病药物倡议的先导优化计划的一部分，开发新的化学实体治疗内脏利什曼病（VL），合成了一系列氨基噻唑并对其体外疗效、溶解度和微粒体稳定性进行了筛选。鉴定具有亚微摩尔活性的铅结构的主要目的实现了。在合成的43个化合物中，有16个化合物对VL的体外活性小于1 μ M。化合物32具有良好的抗利什曼原虫效价（IC50 = 3 nM），除代谢不稳定外，其他性能均良好。阻断化合物32中4-甲氧基吡啶取代基被5-乙氧基取代的代谢软点，得到稳定性提高的化合物36 （IC50 = 280 nM）。为了了解36的处置情况，在小鼠模型中进行了体内药代动力学研究。化合物36清除率高（91 mL/min/kg）；静脉给药（1 mg/kg）后的短半衰期（0.48 h）和口服给药后的暴露（AUC(0-24)）为362 ng h/mL，绝对生物利用度为8%。综上所述，共合成了43种类似物，其中15种化合物在体外系统中表现出非常有效的亚纳摩尔效应，但代谢不稳定性的责任似乎是这类化学物质的主要挑战，仍有待解决。(C) 2015 Elsevier Masson SAS。版权所有。
As part of Drugs for Neglected Diseases initiative's lead optimization program for the development of new chemical entities to treat visceral leishmaniasis (VL), a series of aminothiazoles were synthesized and screened for in vitro efficacy, solubility and microsomal stability. The primary aim of identifying a lead structure with sub-micromolar activity was achieved. Out of 43 compounds synthesized, 16 compounds showed in vitro activity at less than 1 mu M against VL. Compound 32 showed excellent antileishmanial potency (IC50 = 3 nM) and had all the acceptable properties except for metabolic instability. Blocking the metabolic soft spots in compound 32, where the 4-methoxy pyridine substituent was replaced by 5-ethoxy group, led to compound 36 (IC50 = 280 nM) with improved stability. To understand the disposition of 36, in vivo pharmacokinetic study was conducted in a mouse model. Compound 36 showed high clearance (91 mL/min/kg); short half-life (0.48 h) after intravenous administration (1 mg/kg) and exposure (AUC(0-24)) following oral administration was 362 ng h/mL with absolute bioavailability of 8%. To summarize, 43 analogs were synthesized out of which 15 compounds showed very potent sub-nanomolar efficacy in in vitro systems but the liability of metabolic instability seemed to be the major challenge for this chemical class and remains to be addressed. (C) 2015 Elsevier Masson SAS. All rights reserved.