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

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 <b>5h</b> as a novel lead showing potent in vitro activity. Subsequent optimization focused on the modification of two metabolic sites, which provided <b>(4</b><i><b>S</b></i><b>,5</b><i><b>S</b></i><b>)-5i</b>, 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-[(4<i>S</i>,5<i>S</i>)-5-(4fluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]­benzene-1,3-dicarbonitrile <b>(4</b><i><b>S</b></i><b>,5</b><i><b>S</b></i><b>)-5n</b>, 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, Structure–Activity Relationship, and Pharmacological Studies of Novel Melanin-Concentrating Hormone Receptor 1 Antagonists 3-Aminomethylquinolines: Reducing Human Ether-a-go-go-Related Gene (hERG) Associated Liabilities

Recently, we discovered 3-aminomethylquinoline derivative <b>1</b>, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of <b>1</b> was discontinued because <b>1</b> showed potent hERG K⁺ channel inhibition in a patch-clamp study. To decrease hERG K⁺ channel inhibition, experiments with ligand-based drug designs based on <b>1</b> and a docking study were conducted. Replacement of the terminal <i>p</i>-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)­ethyl]­amino group as the amine portion eliminated hERG K⁺ channel inhibitory activity in a patch-clamp study, leading to the discovery of <i>N</i>-{3-[(1<i>R</i>)-1-{[2-(acetylamino)­ethyl]­amino}­ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)­benzamide <b>(</b><i><b>R</b></i><b>)-10h</b>. The compound <b>(</b><i><b>R</b></i><b>)-10h</b> showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of <b>(</b><i><b>R</b></i><b>)-10h</b> was performed to determine the molecule’s absolute configuration

Discovery of [<i>cis</i>-3-({(5<i>R</i>)‑5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro‑1<i>H</i>‑inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5<i>H</i>)‑yl}carbonyl)­cyclobutyl]­acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

A series of tetrahydro­naphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydro­isoquinoline compound <b>1</b> by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound <b>7</b> with a lower log <i>D</i> value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [<i>cis</i>-3-({(5<i>R</i>)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1<i>H</i>-inden-5-yl)­carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6­(5<i>H</i>)-yl}­carbonyl)­cyclobutyl]­acetic acid, TAK-828F (<b>10</b>), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound <b>10</b> exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound <b>10</b> was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases

Discovery of [<i>cis</i>-3-({(5<i>R</i>)‑5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro‑1<i>H</i>‑inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5<i>H</i>)‑yl}carbonyl)­cyclobutyl]­acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

A series of tetrahydro­naphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydro­isoquinoline compound <b>1</b> by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound <b>7</b> with a lower log <i>D</i> value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [<i>cis</i>-3-({(5<i>R</i>)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1<i>H</i>-inden-5-yl)­carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6­(5<i>H</i>)-yl}­carbonyl)­cyclobutyl]­acetic acid, TAK-828F (<b>10</b>), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound <b>10</b> exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound <b>10</b> was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases