Efficient and Stereoselective Syntheses of Isomerically Pure 4‑Aminotetrahydro‑2<i>H</i>‑thiopyran 1‑Oxide Derivatives

Efficient and stereoselective syntheses of isomerically pure 4-aminotetrahydro-2<i>H</i>-thiopyran 1-oxide derivatives have successfully been achieved. Isomerically pure (4-nitrophenyl)­sulfonyltetrahydro-2<i>H</i>-thiopyran 1-oxides were identified by X-ray crystallographic analyses, and isomerically pure sulfoxide derivatives were characterized by ¹H NMR. An oxidation reaction of <i>tert</i>-butyl­(4-nitrophenyl)­sulfonyl­(tetrahydro-2<i>H</i>-thiopyran-4-yl)­carbamate with Oxone provided steric control, affording its trans sulfoxide with high efficiency and selectivity. From the obtained trans sulfoxide derivatives, cis sulfoxide derivatives were synthesized conveniently by a hydrogen chloride catalyzed isomerization

Discovery of Novel 5‑(Piperazine-1-carbonyl)pyridin-2(1<i>H</i>)‑one Derivatives as Orally eIF4A3-Selective Inhibitors

Starting from our previous eIF4A3-selective inhibitor <b>1a</b>, a novel series of (piperazine-1-carbonyl)­pyridin-2­(1<i>H</i>)-one derivatives was designed, synthesized, and evaluated for identification of orally bioavailable probe molecules. Compounds <b>1o</b> and <b>1q</b> showed improved physicochemical and ADMET profiles, while maintaining potent and subtype-selective eIF4A3 inhibitory potency. In accord with their promising PK profiles and results from initial in vivo PD studies, compounds <b>1o</b> and <b>1q</b> showed antitumor efficacy with T/C values of 54% and 29%, respectively, without severe body weight loss. Thus, our novel series of compounds represents promising probe molecules for the in vivo pharmacological study of selective eIF4A3 inhibition

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