The discovery and optimization of Δ-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 5h 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-dicarbonitrile (4S,5S)-5n, endowed with excellent D5D binding affinity, cellular activity, and high oral bioavailability in a mouse. It exhibited robust in vivo hepatic arachidonic acid/dihomo-γ-linolenic acid ratio reduction (a target engagement marker) in an atherosclerosis mouse model. Finally, an asymmetric synthetic procedure for this compound was established.

中文翻译：

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3,5-二苯基-4-甲基-1,3-恶唑烷-2-酮作为新型，有效和口服可用的Δ-5去饱和酶（D5D）抑制剂的发现

描述并优化了Δ-5去饱和酶（D5D）抑制剂。1,3-恶唑烷-2-酮骨架的研究受到药效团模型的启发，该药效团模型是由几种命中化合物的共同特征构建而成的，从而可在5h内鉴定出3,5-二苯基-1,3-恶唑烷-2-酮作为一种新型的铅，显示出强大的体外活性。随后的优化集中在两个代谢位点的修饰上，这提供了（4 S，5 S）-5i，这是一种具有改善的代谢稳定性的衍生物。此外，在上部苯基部分添加取代基进一步增强了内在活性，这导致了5-[（4 S，5 S）-5-（4氟苯基）-4-甲基-2-氧代-1,3-恶唑烷-3-基]苯-1,3-二碳腈（4 S，5 S）-5n，具有出色的D5D结合亲和力，细胞活性和小鼠的高口服生物利用度。在动脉粥样硬化小鼠模型中，它表现出强劲的体内肝花生四烯酸/二高-γ-亚麻酸比率降低（目标参与标记）。最后，建立了该化合物的不对称合成方法。