Kouhei Asano

Coenzyme A: diacylglycerol acyltransferase 1 inhibitor ameliorates obesity, liver steatosis, and lipid metabolism abnormality in KKAy mice fed high-fat or high-carbohydrate diets.

Coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) is 1 of the 2 known DGAT enzymes that catalyze the final and only committed step in triacylglycerol synthesis; this enzyme is considered to be a potential therapeutic target in metabolic disorders such as obesity and its related lipid abnormalities. Compound-Z, a novel specific small-molecule DGAT1 inhibitor, significantly reduced adipose tissue weight and tended to hepatic lipid accumulation in genetically obese KKAy mice. These actions were shown to almost the same extent in both a high-fat feeding condition in which triacylglycerols are synthesized mainly via exogenous fatty acid and a low-fat, high-carbohydrate feeding condition in which triacylglycerols are synthesized mainly via de novo fatty acid synthesis. This inhibitor also significantly reduced plasma and/or hepatic cholesterol levels in KKAy mice in a high-fat feeding condition. This cholesterol-lowering effect was suggested to be due to mainly decreases in cholesterol absorption from the small intestine. These results suggest that Compound-Z is a promising and attractive agent not only for the treatment of obesity but also hepatic steatosis and circulating lipid abnormalities that are the leading causes of atherosclerosis.

Design, synthesis, and structure-activity relationships of dihydrofuran-2-one and dihydropyrrol-2-one derivatives as novel benzoxazin-3-one-based mineralocorticoid receptor antagonists.

Dihydrofuran-2-one and dihydropyrrol-2-one derivatives were identified as novel, potent and selective mineralocorticoid receptor (MR) antagonists by the structure-based drug design approach utilizing the crystal structure of MR/compound complex. Introduction of lipophilic substituents directed toward the unfilled spaces of the MR and identification of a new scaffold, dihydropyrrol-2-one ring, led to potent in vitro activity. Among the synthesized compounds, dihydropyrrol-2-one 11i showed an excellent in vitro activity (MR binding IC50=43nM) and high selectivity over closely related steroid receptors such as the androgen receptor (AR), progesterone receptor (PR) and glucocorticoid receptor (GR) (>200-fold for AR and PR, 100-fold for GR).

Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists

In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.

Discovery of a novel B-cell lymphoma 6 (BCL6)–corepressor interaction inhibitor by utilizing structure-based drug design

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6-corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC50=0.10µM, cell-based mammalian two-hybrid [M2H] assay IC50=0.72µM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies.