Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides.
Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides.
复制标题
口服生物可利用的抗利什曼尼尔 2,4,5-三取代苯甲酰胺的优化。
DOI：
10.1021/acs.jmedchem.3c00056
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发表时间：
2023
影响因子：
7.3
通讯作者：
Guy,RKiplin
中科院分区：
文献类型：
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作者：
Kim,HoShin;Ortiz,Diana;Kadayat,TaraMan;Fargo,CorinneM;Hammill,JaredT;Chen,Yizhe;Rice,AmyL;Begley,KristinL;Shoeran,Gaurav;Pistel,William;Yates,PhillipA;Sanchez,MarcoA;Landfear,ScottM;Guy,RKiplin
利什曼病是由利什曼寄生虫引起的一种被忽视的热带病，每年影响全世界100多万人。由于成本高、不良反应严重、疗效差、使用困难以及对所有已批准的疗法出现耐药性，利什曼病的治疗选择有限。我们发现2,4,5-三取代苯酰胺(4)具有有效的抗利什曼原虫活性，但水溶解度差。在此，我们揭示了我们的优化物理化学和代谢性质的2,4,5-三取代苯甲酰胺保持效力。广泛的结构-活性和结构-性质关系研究允许选择具有合适效力、微粒体稳定性和改善溶解度的早期先导物。早期铅79表现出80%的口服生物利用度，并能有效阻断利什曼小鼠模型的增殖。这些苯甲酰胺早期先导物适合开发为口服抗利什曼病药物。
Leishmaniasis, a neglected tropical disease caused byLeishmaniaspecies parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure–activity and structure–property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead79exhibited an 80% oral bioavailability and potently blocked proliferation ofLeishmaniain murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.