Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
J Med Chem. 2017 Nov 9;60(21):8963-8981. doi: 10.1021/acs.jmedchem.7b01210. Epub 2017 Oct 31.
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.
Δ-5 去饱和酶（D5D）抑制剂的发现和优化。对 1,3-恶唑烷-2-酮骨架的研究受到了从几个命中化合物的共同特征构建的药效团模型的启发，导致鉴定出 3,5-二苯基-1,3-恶唑烷-2-酮 5h 作为一种新型的具有潜在活性的先导化合物。随后的优化集中在两个代谢部位的修饰上，这提供了（4S,5S）-5i，一种具有改善代谢稳定性的衍生物。此外，在上苯基部分引入取代基进一步增强了内在活性，从而发现了 5-[(4S,5S)-5-(4-氟苯基)-4-甲基-2-氧代-1,3-恶唑烷-3-基]苯并[1,3]-二氰基（4S,5S）-5n，具有优异的 D5D 结合亲和力、细胞活性和在小鼠中的高口服生物利用度。它在动脉粥样硬化小鼠模型中表现出对肝花生四烯酸/二同型-γ-亚麻酸比率降低（靶标结合标记）的强大体内活性。最后，建立了该化合物的不对称合成方法。
