15 research outputs found
Essential Role of IκB Kinase α in Thymic Organogenesis Required for the Establishment of Self-Tolerance
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><sub>a</sub> < 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><sub>a</sub> < 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"
Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition
Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation of mutagenicity in Ames test
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<sup>+</sup> channel inhibition in a patch-clamp
study. To decrease hERG K<sup>+</sup> 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<sup>+</sup> 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