Discovery of 3,5-Diphenyl-4-methyl-1,3-oxazolidin-2-ones as Novel, Potent, and Orally Available Δ-5 Desaturase (D5D) Inhibitors

Abstract

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.

Synthesis of Chiral 5‐Aryl‐2‐oxazolidinones via Halohydrin Dehalogenase‐Catalyzed Enantio‐ and Regioselective Ring‐Opening of Styrene Oxides

“…As shown in Table , regardless of the electronic nature of the substituents, all substrates could be smoothly transformed into the corresponding chiral 5‐aryl‐2‐oxazolidinones ( R )‐ 2 a – 2 i in moderate to good ee (74–90%), as well as moderate to excellent yields (32–47%). Noteworthy, enantiopure para ‐F substituted 5‐aryl‐2‐oxazolidinones 2 f is an important skeleton structure for the discovery of Δ‐5 desaturase inhibitors . Additionally, the regioselectivities of the reactions were determined via analysis of the ratio of 5‐aryl‐2‐oxazolidinones 2 (C β ‐attack) to 4‐aryl‐2‐oxazolidinones 3 (C α ‐attack) by 1 H NMR.…”

“…Noteworthy, enantiopure para-F substituted 5-aryl-2oxazolidinones 2 f is an important skeleton structure for the discovery of Δ-5 desaturase inhibitors. [10] Additionally, the regioselectivities of the reactions were determined via analysis of the ratio of 5-aryl-2oxazolidinones 2 (C β -attack) to 4-aryl-2-oxazolidinones 3 (C α -attack) by 1 H NMR. The results revealed that the HheC exhibited a poor to good C β -position regioselectivity toward these aromatic epoxides ( Table 3).…”

Delta-5-desaturase: A novel therapeutic target for cancer management

“…The benefit of RNAi-based genetical knockdown of D5D, such as siRNA, shRNA, and RNA nanoparticles, have been confirmed in colon, pancreatic, breast, and lung cancers in vitro and in vivo [ 6 , 7 , [83] , [84] , [85] , [86] , 89 ]. Additionally, small molecule D5D inhibitors also have been identified in cell-based or rat liver microsomes assays, including sesamin, curcumin, D5D-IN-326, CP-24879, iminodibenzyl, etc [ 94 , 95 , 110 , 112 , 115 , 140 ]. Although iminodibenzyl efficiently suppresses lung cancer cell growth and metastasis [115] , more studies need to be done to further explore the effect and mechanisms of other D5D small molecule inhibitors in cancer.…”

“…Given that inflammatory cytokines, such as TNF-α and NF-κB, are important downstream targets of sesamin and curcumin [ 108 , 109 ], these natural inhibitors may affect inflammatory tumor microenvironment (TME) via regulating D5D activity. Furthermore, several selective D5D inhibitors have been identified by Takeda Pharmaceutical Company, such as D5D-IN-326, T-3364366, and 3,5-diphenyl-4-methyl-1,3-oxazolidin-2-ones; however, the effect and mechanism of these molecules have only been evaluated in metabolic diseases (such as insulin resistance, obesity, and atherosclerosis) rather than cancer [110] , [111] , [112] , [113] . Additionally, another molecule iminodibenzyl has recently been found as a promising D5D inhibitor.…”

One‐Step Synthesis of 3,4‐Disubstituted 2‐Oxazolidinones by Base‐Catalyzed CO2 Fixation and Aza‐Michael Addition

“…The most conventional 2‐oxazolidinones synthesis is carried out by cyclizing amino alcohols with phosgene, followed by C−N coupling (Scheme A) . These steps may also be executed in reverse order .…”