2 research outputs found
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)Âpyridin-2Â(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
Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic Acids: Discovery of a Non-Free Fatty Acid-Like, Highly Bioavailable G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist as a Glucose-Dependent Insulinotropic Agent
G protein-coupled receptor 40 (GPR40)/free fatty acid
receptor
1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified
glucose-stimulated insulin secretion in pancreatic β-cells.
We previously identified (2,3-dihydro-1-benzofuran-3-yl)Âacetic acid
derivative <b>2</b> as a candidate, but it had relatively high
lipophilicity. Adding a polar functional group on <b>2</b> yielded
several compounds with lower lipophilicity and little effect on caspase-3/7
activity at 30 μM (a marker of toxicity in human HepG2 hepatocytes).
Three optimized compounds showed promising pharmacokinetic profiles
with good in vivo effects. Of these, compound <b>16</b> had
the lowest lipophilicity. Metabolic analysis of <b>16</b> showed
a long-acting PK profile due to high resistance to β-oxidation.
Oral administration of <b>16</b> significantly reduced plasma
glucose excursion and increased insulin secretion during an OGTT in
type 2 diabetic rats. Compound <b>16</b> (TAK-875) is being
evaluated in human clinical trials for the treatment of type 2 diabetes