Yoshihiko Odagaki

X-Ray structure of the α-cyclodextrin–ferrocene (2 : 1) inclusion compound

The crystal structure of the α-cyclodextrin–ferrocene (2 : 1) inclusion compound has been determined by an X-ray analysis which shows that the ferrocene molecule with approximate D5d symmetry is encapsulated by the dimer of the α-cyclodextrins in a tail-to-tail orientation and inclined by 42° relative to the six-fold axes of the α-cyclodextrins of the dimer.

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.

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.

A practical synthesis and biological evaluation of 9-halogenated PGF analogues.

A series of 9-halo PGF analogues 1-2 and 5-13 were synthesized and biologically evaluated. Among the compounds, 2 was the best EP2-receptor agonist. A practical method of synthesizing 2 via the Julia olefination of an aldehyde 3 with an optically active sulfone 4, which was prepared by Sharpless asymmetric epoxidation of 15, was developed. Other 9-halogenated PGF analogues were synthesized essentially by the same procedure and evaluated. The absolute configuration of 16-OH of 2 was determined as S by the X-ray analysis of a salt consisting of a 1/1 molar ratio of 2 and L-lysine.

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.

Discovery of new orally active prostaglandin D2 receptor antagonists.

To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure-activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD(2)-induced and OVA-induced vascular permeability in guinea pig conjunctiva.

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).

Protective effects of microglia-conditioned medium (MCM) against NMDA-induced dendritc injury through an inhibition of non-selective cation conductance

By the use of a transient 90-min middle cerebral artery occlusion (MCAO) model of rats, we have shown that highly proliferative macrophage-like cells derived from bone marrow, started to accumulate in 2 days post reperfusion (2 dpr), and their number peaked at 7 dpr. Such macrophage-like cells expressed Iba1 and NG2 proteoglycan, therefore they were termed BINCs (Brain Iba1+/NG2+ Cells). Since the cells elicited ameliorative effects on the ischemic brains, some methods that enhance the accumulation of BINCs in ischemic lesions may become an effective treatment. However, it is an open question what kinds of factors are responsible for the recruitment of BINCs or their progenitors from the bone marrow to the ischemic brain lesions. In this study, we focused on fractalkine and MCP-1 as candidate factors responsible for the recruitment. BINCs were isolated from the cerebral ischemic lesion at 7 dpr, and mRNAs encoding MCP-1 and fractalkine as well as their receptors CCR2 and CX3CR1 were quantified using real-time RT-PCR. The expression levels of mRNAs by BINCs were compared with those by primary astrocytes and microglia. BINCs expressed CCR2 and CX3CR1 at the highest levels among the three types of cells, whereas astrocytes their ligands fractalkine and MCP-1 at the highest levels. Kinetic study using in vivo samples revealed that ischemic brain tissue contained significant level of mRNAs of both chemokines by 2 dpr, but the expressed level of the mRNAs decreased in time by 5dpr. The chemokines induced directed chemotaxis of BINCs, as revealed by migration assay using Boyden chambers. Taken together the present data and our previous study showing that BINCs or BINC progenitors may invade into ischemic brain tissue by 2dpr, it is probable that the two chemokines are responsible for the recruitment of BINCs or BINC progenitor from bone marrow.

Regio- and stereoselective ring-opening of chiral 1,3-oxazolidin-2-one derivatives by organocopper reagents provides novel access to di-, tri- and tetra-substituted alkene dipeptide isosteres

Organocopper-mediated alkylation of β-( N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates has been intensively investigated. Alkylation proceeded regio- and stereoselectively by anti- SN2′ ring-opening to provide a new route to the synthesis of ψ[( E)-CHCH]-, ψ[( E)-CMeCH]- and ψ[( E)-CMeCMe]- type alkene dipeptide isosteres from chiral amino acid derivatives. These resulting agents are potential mimetics of type II and type II′ β-turn substructure.