Yasunori Aoyama

Design, synthesis and pharmacological evaluation of 3-benzylazetidine-2-one-based human chymase inhibitors

3-Benzylazetidine-2-one derivatives were designed and evaluated as a novel series of chymase inhibitors. Structure-activity relationship studies of 3-benzylazetidine-2-ones led to compounds 23, which exhibited 3.1 nM inhibition of human chymase and enhancement of stability in human plasma (t(1/2) 6h).

Total synthesis of human chymase inhibitor methyllinderone and structure–activity relationships of its derivatives

Total synthesis of human chymase inhibitor methyllinderone has been achieved in only four steps with an overall yield of 21% from dimethyl squarate. We developed an efficient synthetic method for obtaining methyllinderone derivatives and found the active compound. In addition, we propose the inhibition mechanism of the active compound against human chymase using calculations.

Synthesis and structure-activity relationships of a new class of 1-oxacephem-based human chymase inhibitors.

1-Oxacephem derivatives were synthesized and evaluated as a novel series of chymase inhibitors. Structure-activity relationship studies of 1-oxacephems led to compound 34, which exhibited 6 nM inhibition of human chymase and high selectivity for human chymase compared to other serine enzymes.

1-Oxacephem-Based Human Chymase Inhibitors: Discovery of Stable Inhibitors in Human Plasma

1-Oxacephem derivatives were evaluated as a novel series of chymase inhibitors. The structure-activity relationship studies of 1-oxacephems led to compounds 15, which exhibited 27 nM inhibition of human chymase and improvement of stability in human plasma (t 1/2 1.5 h).

Inhibition of serine proteases: activity of 1,3-diazetidine-2,4-diones.

The present work demonstrates that the 1,3-diazetidine-2,4-dione nucleus is effective as a scaffold of serine protease inhibitors. Compound 1 displayed high activity against human cathepsin G and alpha-chymotrypsin (0.39, 0.69 nM). Compound 6 exhibited 0.85 nM inhibition of human chymase. Compound 10 was a selective inhibitor against human neutrophil elastase.

Non-peptidic chymase inhibitors

Human chymase is a chymotrypsin-like serine protease. Although the physiological and pathological roles of chymase have not been fully elucidated, recent studies have implicated its involvement in numerous physiological functions. Preliminary results suggest a wide therapeutic utility for chymase inhibitors in disorders such as heart failure, hypertension, chronic inflammation, allergy, dermatitis, rheumatoid arthritis and asthma. This review will focus on patent applications describing non-peptidic chymase inhibitors published within the last five years.

Effects of trifluoroethanol as a co-solvent on the electrochemical oxidation of hardly oxidizable organic compounds

2,2,2-Trifluoroethanol was found to be a suitable co-solvent for the electrochemical oxidation of organic compounds such as cyclic ethers, γ-butyrolactone derivatives, primary alcohols, and toluenes substituted with electron-withdrawing groups, all of which were resistant toward oxidation in methanol. The oxidation products could be utilized as worthwhile synthetic intermediates.

Structure and reactivity of reconstituted myoglobins: interaction between protein and polar side chain of chemically modified hemin

We prepared the C2-symmetrical hemin, 1,2,3,4-tetraethyl-5,8-dimethyl-6,7-dipropionate porphyrin iron complex (1), and its derivatives 2–4 conjugated with glycine, valine or phenylalanine at the terminal of one of two peripheral proprionates through amide linkage. These hemins were incorporated into apomyoglobin from horse heart and the reconstituted proteins were characterized by 1H NMR spectroscopy. Replacement of one propionate in the hemin with propionamide conjugated with amino acid has no serious effect on the structure of the heme pocket, and the chemical shifts of heme 5-CH3 and Ile99 protons in the cyanometmyoglobins are comparable with those in reference myoglobin with 1. Upon reconstitution with 2–4, 1H NMR spectra show two-set heme orientations in the heme pocket in a ratio of 1:0.17∼1:0.40 at equilibrium. Thermodynamic analysis based on NMR results indicates that propionamide-Lys45 pairing is more stable by ∼0.2 kcal mol−1 than Ser92/His97 pairing, whereas propionate-Lys45 pairing is less stable by ∼0.6 kcal mol−1 than Ser92/His97 pairing. The autoxidation rates of oxymyoglobin reconstituted with 2–4 are comparable with that of reference oxymyoglobin with 1. Furthermore, the kinetic analysis suggests that the oxyform of 6-propionamide-7-methyl-heme 5 is more stable than that of 6-propionate-7-methyl-heme 6 in myoglobin owing to the different interaction of polar side chain with protein.

Stereoselective homocoupling of phenylacetic acid derivatives utilizing electrochemically generated base

Abstract Electrochemically generated base (EGB) was cathodically prepared from pyrrolidone, and it was used as an efficient base to generate an anion of methyl phenylacetate. The anion was oxidized by iodine to afford dimethyl 2, 3-diphenylsuccinate in high yield and high dl selectivity. Optically active 2, 3-diphenylsuccinic acid derivative was prepared by this EGB/iodine method. The oxidative homocoupling of methyl phenylacetate was also achieved with a catalytic amount of iodine by utilizing an electrochemical mediator system.