Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1‑(Imidazo[1,2‑<i>a</i>]pyridin-6-yl)pyridin-2(1<i>H</i>)‑one Derivatives

Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of p<i>K</i>_a < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo­[1,2-<i>a</i>]­pyridine ring (represented in compounds <b>6a</b> and <b>6b</b>), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)­oxy]-1-(2-cyclopropyl-3-methylimidazo­[1,2-<i>a</i>]­pyridin-6-yl)­pyridin-2­(1<i>H</i>)-one <b>10a</b>. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1‑(Imidazo[1,2‑<i>a</i>]pyridin-6-yl)pyridin-2(1<i>H</i>)‑one Derivatives

Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of p<i>K</i>_a < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo­[1,2-<i>a</i>]­pyridine ring (represented in compounds <b>6a</b> and <b>6b</b>), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)­oxy]-1-(2-cyclopropyl-3-methylimidazo­[1,2-<i>a</i>]­pyridin-6-yl)­pyridin-2­(1<i>H</i>)-one <b>10a</b>. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats

Wide-bandgap semiconductor materials: For their full bloom

Wide-bandgap semiconductors are expected to be applied to solid-state lighting and power devices, supporting a future energy-saving society. While GaN-based white LEDs have rapidly become widespread in the lighting industry, SiC- and GaN-based power devices have not yet achieved their popular use, like GaN-based white LEDs for lighting, despite having reached the practical phase. What are the issues to be addressed for such power devices? In addition, other wide-bandgap semiconductors such as diamond and oxides are attracting focusing interest due to their promising functions especially for power-device applications. There, however, should be many unknown phenomena and problems in their defect, surface, and interface properties, which must be addressed to fully exploit their functions. In this review, issues of wide-bandgap semiconductors to be addressed in their basic properties are examined toward their "full bloom"

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