Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Eur J Med Chem. 2021 Jan 1;209:112914. doi: 10.1016/j.ejmech.2020.112914. Epub 2020 Oct 10.
Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.
先前的研究表明,具有联苯侧链的抗结核 7 位取代的 2-硝基咪唑并[2,1-b][1,3]恶嗪具有很强的抗利什曼原虫作用,这促使我们开发了一种新的治疗内脏利什曼病的临床候选药物(DNDI-0690)。在一个合作的后备计划中,一种具有类似活性的外消旋单芳基先导化合物(3)在小鼠中具有相当的活性,但 hERG 风险更大,这成为我们追求具有良好溶解性和安全性的有效第二代类似物的起点。不对称合成及其对映异构体的评估首先确定了体内疗效的手性偏好取决于物种,并且两种形式都不能降低 hERG 风险。然而,与我们在结构相关系列中的发现一致,疏水性较低的杂芳基醚提供了显著的溶解性增强(高达 16 倍),同时减弱了 hERG 抑制。一种有前途的吡啶衍生物(49)在小鼠中具有 100%的口服生物利用度,当在利什曼原虫感染的小鼠模型中以 50mg/kg 的剂量给药时,可将寄生虫负荷减少 96%。