Nobuyuki Hamanaka

The crystal structure of the complex of non-peptidic inhibitor of human neutrophil elastase ONO-6818 and porcine pancreatic elastase.

The crystal structure of a new inhibitor of human neutrophil elastase (HNE), N-[2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-(IRS)-1-(methylethyl)-2-oxoethyl]-2-(5-amino-6-oxo-2-phenyl-6H-pyrimidin-1-ly)acetamide (ONO-6818, 1) complexed to porcine pancreatic elastase (PPE) has been determined at 1.86 A resolution. Analytical results provided evidence of a 1:1 complex in which the electrophilic ketone of 1 covalently bound to O gamma of Ser195 at the active site of PPE. The role of the unique electron-withdrawing ketone of 1 has been elucidated.

Molecular design of novel PGI2 agonists without PG skeleton. III

Abstract Syntheses of novel prostaglandin (PG) mimetics without PG skeleton are described, and the structure-activity relationships are discussed. Highly potent compounds could be obtained when the PG analog 3 was modified by removing and reconstructing the cyclopentane ring, and changing the allylic alcohol in the natural PGs.

Synthesis of structural analogues of leukotriene B4 and their receptor binding activity.

Structural analogues of leukotriene B4 (LTB4) were designed based on the plausible conformation of LTB4 (1). Joining C-7-C-9 of the conformer A or B into an aromatic ring system led to the discovery of benzene analogues 2, 4 and 6a. Joining C-4-C-9 of the conformer C or D into an aromatic ring system led to the discovery of analogues 3, 5 and 7. The compounds examined in this study were evaluated as to their inhibition of [3H] LTB4 binding to human neutrophils, and by a secondary intact human neutrophil functional assay for agonist/antagonist activity. The first analogues prepared, compounds 2-7, demonstrated moderate potency in the LTB4 receptor binding assay. The modification of these compounds by the introduction of another substituent into the aromatic ring produced a marked increase in receptor binding (28c, IC50 = 0.020 microM; 38c, IC50 = 0.020 microM; 52a, IC50 = 0.020 microM; 52b, IC50 = 0.018 microM). Most of these structural analogues of LTB4 demonstrated agonist activity. Of the analogues prepared in this study, only compound 57 demonstrated weak LTB4 receptor antagonist activity, at 10 microM.

Pharmacological evaluation of combined PGI2 agonists/thromboxane synthase inhibitors. I

Abstract By incorporation of a pyridine moiety into compounds shown to be PGI 2 agonists, we have synthesized a series of compounds which also show potent thromboxane synthase inhibitory activity. Agents 9 and 14 with the 3-substituted pyridine moiety show a combined properties of PGI 2 agonist and TXA 2 synthase inhibitor.

Conformation of (Z)-3-carboxymethyl-[(2E)-2-methyl-3-phenylpropenylidene]rhodanine (epalrestat), a potent aldose reductase inhibitor: X-ray crystallographic, energy calculational, and nuclear magnetic resonance studies

In order to examine the conformational characteristics of aldose reductase inhibitors, the conformational analysis of epalrestat (ONO-2235) has been carried out by X-ray crystallographic, energy calculational, and nuclear magnetic resonance methods. The chemical structure which had previously been proposed for epalrestat has been revised by the X-ray single-crystal analysis. The extremely planar conformation observed in the crystal structure is shown to be energetically the most stable form and is the predominant form in solution. The characteristic conformation is discussed with respect to the aldose reductase inhibitory activity.

Palladium(0) catalyzed reactions of 1,4-epiperoxides

The Pd(PPh 3 ) 4 catalyzed reaction of 2,3-saturated and 2,3-unsaturated 1,4-epiperoxides proceeds by courses markedly different from those of the previously reported transition metal catalyses. The Pd(0)-promoted reaction of 2,3-saturated epiperoxides gives the corresponding 4-hydroxy ketones and 1,4-diols as the major products. From 2,3-dedihydroepiperoxides are formed the corresponding 4-hydroxy enones, syn-1,2;3,4-diepoxides, and 1,4-diols. The results are interpreted in terms of competing Pd(0)/Pd(II) and Pd(0)/Pd(I) exchange mechanisms

Stereoselective synthesis of a set of two functionalized (E)-alkene dipeptide isosteres of L-amino acid-L-Glu and L-amino acid-D-Glu

Treatment of N-arylsulfonyl-γ,δ-cis- or -trans-γ,δ-epimino (E)-α,β-enoates with HCl–1,4-dioxane affords regio- and stereo-selective ring-opened products, δ-aminated γ-chloro-α,β-enoates. This ring-opening reaction provides a useful method for the stereoselective synthesis of a set of diastereomeric (L-Xaa, L-Glu)-type and (L-Xaa, D-Glu)-type (E)-alkene dipeptide isosteres (EADIs) from a single substrate of γ,δ-epimino (E)-α,β-enoate using organozinc–copper reagents.

Cunninghamic acids A and B, novel bis(labdane)-type diterpenoids from Cunninghamia lanceolata

Abstract Cunninghamic acids A and B, two novel bis(labdane)-type diterpenoids have been isolated as their methyl esters from the cones of Cunninghamia lanceolata and their structures have been elucidated by extensive analysis of 2D NMR spectroscopy.

Photo-degradation products of pramipexole

Two pyrrolidine compounds (1 and 2) were isolated from photo-degradation of Bi-Sifrol tablets. Compound 1 was esterified to p-bromophenacyl ester as single-crystal, and then the structure was elucidated by single-crystal X-ray study. Compound 2 was determined by 2D NMR and mass spectra. Otherwise, we established that the photo-degradation of pramipexole was smoothly carried out in the methanol solution, and elucidate the degradation mechanism.

Trisubstituted benzene leukotriene B4 receptor antagonists: Synthesis and structure-activity relationships

A series of trisubstituted benzenes which demonstrate leukotriene B4 (LTB4, 1) receptor affinity was prepared. Previous trisubstituted benzenes from our laboratory showed high affinity to the LTB4 receptor but demonstrated agonist activity in functional assays. Compound 3a, the initial lead compound of this new series, showed only modest affinity (IC50 = 0.20 microM). However, 3a was a receptor antagonist with no demonstrable agonist activity up to 30 microM. Further modification of the lipid tail and aryl head groups region led to the discovery of 3b (ONO-4057). This compound, free of agonist activity, possesses high affinity to the LTB4 receptor (Ki = 3.7 +/- 0.9 nM).