Structure-Activity Relationship Study and Biological Evaluation of 2-(Disubstituted phenyl)-indole-5-propanoic Acid Derivatives as GPR40 Full Agonists.

G-protein-coupled receptor 40 (GPR40) is considered as an attractive drug target for treating type 2 diabetes, owing to its role in the free fatty acid-mediated increase in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To identify a new chemotype of GPR40 agonist, a series of 2-aryl-substituted indole-5-propanoic acid derivatives were designed and synthesized. We identified two GPR40 agonist lead compounds- (3-[2-(4-fluoro-2-methylphenyl)-1-indol-5-yl]propanoic acid) and (3-[2-(2,5-dimethylphenyl)-1-indol-5-yl]propanoic acid), having GSIS and glucagon-like peptide 1 secretory effects.

Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis.

The histamine H4 receptor (H4R), a member of the G-protein coupled receptor family, has been considered as a potential therapeutic target for treating atopic dermatitis (AD). A large number of H4R antagonists have been disclosed, but no efficient agents controlling both pruritus and inflammation in AD have been developed yet. Here, we have discovered a novel class of orally available H4R antagonists showing strong anti-itching and anti-inflammation activity as well as excellent selectivity against off-targets.

SAR Studies of Indole-5-propanoic Acid Derivatives To Develop Novel GPR40 Agonists.

G-protein coupled receptor 40 (GPR40) has been considered to be an attractive drug target for the treatment of type 2 diabetes because of its role in free fatty acids-mediated enhancement of glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. A series of indole-5-propanoic acid compounds were synthesized, and their GPR40 agonistic activities were evaluated by nuclear factor of activated T-cells reporter assay and GSIS assay in the MIN-6 insulinoma cells. Three compounds, (EC = 58.

Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors.

A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors is described. Molecular design was performed using X-ray cocrystal structures of the lead compound CH5015765 and natural Hsp90 inhibitor geldanamycin with Hsp90. We optimized affinity to Hsp90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors and identified CH5138303.

Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design.

Heat shock protein 90 (Hsp90) is a molecular chaperone which regulates maturation and stabilization of its substrate proteins, known as client proteins. Many client proteins of Hsp90 are involved in tumor progression and survival and therefore Hsp90 can be a good target for developing anticancer drugs. With the aim of efficiently identifying a new class of orally available inhibitors of the ATP binding site of this protein, we conducted fragment screening and virtual screening in parallel against Hsp90.