Discovery of 3,5-Diphenyl-4-methyl-1,3-oxazolidin-2-ones as Novel, Potent, and Orally Available Δ-5 Desaturase (D5D) Inhibitors
Discovery of 3,5-Diphenyl-4-methyl-1,3-oxazolidin-2-ones as Novel, Potent, and Orally Available Δ-5 Desaturase (D5D) Inhibitors
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DOI：
10.1021/acs.jmedchem.7b01210
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发表时间：
2017-11-09
影响因子：
7.3
通讯作者：
Matsunaga, Nobuyuki
中科院分区：
文献类型：
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作者：
Fujimoto, Jun;Okamoto, Rei;Matsunaga, Nobuyuki
介绍了Delta-5去饱和酶(D5D)抑制剂的发现和优化。对1，3-恶唑烷-2-酮支架的研究灵感来自于根据几种Hit化合物的共同特征构建的药效团模型，从而确定了3，5-二苯基-1，3-恶唑烷-2-酮Sh是一种具有潜在体外活性的新的先导化合物。随后的优化集中在两个代谢位点的修饰上，这为(4S，5S)-5I提供了一种具有更好代谢稳定性的衍生物。此外，在上苯基上添加取代基进一步增强了内源活性，从而发现了5-[(4S，5S)-5-(4fluorophenyl)-4-methyl-2-oxo-1，3-oxazolidin-3-yl]benzene-1，3-clicarbonitrile(4S，5S)-5N，它具有良好的DSD结合亲和力、细胞活性和较高的小鼠口服生物利用度。在动脉粥样硬化小鼠模型中，它在体内显示出强劲的肝脏花生四烯酸/双高-伽马-亚麻酸比率降低(靶标记物)。最后，建立了该化合物的不对称合成工艺。
The discovery and optimization of Delta-5 desaturase (D5D) inhibitors are described. Investigation of the 1,3-oxazolidin-2-one scaffold was inspired by a pharmacophore model constructed from the common features of several hit compounds, resulting in the identification of 3,5-diphenyl-1,3-oxazolidin-2-one Sh as a novel lead showing potent in vitro activity. Subsequent optimization focused on the modification of two metabolic sites, which provided (4S,5S)-5i, a derivative with improved metabolic stability. Moreover, adding a substituent into the upper phenyl moiety further enhanced the intrinsic activity, which led to the discovery of 5-[(4S,5S)-5-(4fluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]benzene-1,3-clicarbonitrile (4S,5S)-5n, endowed with excellent DSD binding affinity, cellular activity, and high oral bioavailability in a mouse. It exhibited robust in vivo hepatic arachidonic acid/dihomo-gamma-linolenic acid ratio reduction (a target engagement marker) in an atherosclerosis mouse model. Finally, an asymmetric synthetic procedure for this compound was established.