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)­acetic 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

L'Auto-vélo : automobilisme, cyclisme, athlétisme, yachting, aérostation, escrime, hippisme / dir. Henri Desgranges

27 mars 19301930/03/27 (A31,N10694)

Map of the newly discovered hydrothermal vent fields.

<p>(A) Locations of the Dodo Great Lava Plain and Roger Plateau in the Rodriguez Segment (Segment 15 and 16 of the CIR). (B) Locations of the Dodo and Solitaire hydrothermal fields on the Dodo Great Lava Plain and Roger Plateau, respectively.</p

Chemical compositions of hydrothermal fluids from the Dodo and Solitaire hydrothermal fields.

<p>(A) Chlorine and (B) H₂ concentrations are plotted against average fluid temperature during each sampling. Blue open circles with dashed lines and red open squares with dotted lines represent the Dodo and Solitaire fluids, respectively. Gray horizontal line in (A) indicates seawater level (560 mmol/kg).</p

Photographs of macromorphology and of microscopic and SEM-EDS analyses of sclerites from the two morphotypes of ‘scaly-foot’ gastropods.

<p>(A), (B) Photographs of the two morphotypes of ‘scaly-foot’ gastropods. Bar indicates 1 cm. (C), (F) Optical micrographs of the polished surface of the sclerite sections. (D), (G) Elemental mapping of iron in the same sections by SEM-EDS. (E), (H) Elemental mapping of sulfur by SEM-EDS. The black-white-green colors indicate the intensity of each element.</p

Opercular plates of the ‘scaly-foot’ gastropod.

<p>(A) Ventral view of juvenile of ‘scaly-foot’ gastropod with operculum indicated by red arrowheads. Shell length is about 2 mm. (B) Opercula of adult ‘scaly-foot’ gastropods indicated by red arrowheads. The scale bar represents 5 mm.</p

Size distributions of ‘scaly-foot’ gastropods at the Kairei (A) and Solitaire (B) fields.

<p>The average sizes of the Kairei and Solitaire populations were 37.87 mm and 31.95 mm, respectively.</p

Parsimonious networks of the ‘scaly-foot’ gastropods at the Solitaire and Kairei fields, based on sequences of nuclear SSU rRNA gene (A) and mitochondrial COI gene (B).

<p>White circles indicate the haplotypes from the Solitaire field and black circles indicate those from the Kairei field.</p

Photographs of black smoker chimneys and associated brownish colored spots.

<p>(A) Tsukushi-2 chimneys on basaltic sheet flow lava at the Dodo hydrothermal field. <i>A. rodriguezensis</i> is sparsely distributed on the lava. (B) A brownish colored spot in the stained lava area surrounding the Dodo hydrothermal field. (C) Toukon-3 chimneys at the Solitaire hydrothermal field. The chimney walls were partially covered with swarms of <i>R. kairei</i>. The animals aggregating around the diffuse fluids are visible in the background to the left of the frame.</p

List of the observed and/or sampled animals in the Dodo and Solitaire fields.

<p>List of the observed and/or sampled animals in the Dodo and Solitaire fields.</p