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.

Highly potent PDE4 inhibitors with therapeutic potential.

The hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system prompted us to design and synthesize a hydrophilic piperidine analog to improve the side effect profile of Ariflo 1, which is an orally active second-generation PDE4 inhibitor. During evaluation of various water-soluble piperidine analogs, 2a-b, 11b-14b, and 17a showed therapeutic potential in cross-species comparison studies. The following three findings were obtained: (1) The hydroxamic acid group, a well known metal chelator, caused a marked increase of inhibitory activity.

Design, synthesis, and biological evaluation of new phosphodiesterase type 4 inhibitors.

The design, synthesis, and biological evaluation of new phosphodiesterase type 4 inhibitors, which possess new templates instead of a cyclohexane ring, are described. The mode of interaction with the enzyme is discussed based on the structure-activity relationship (SAR) data obtained for the synthesized inhibitors. Furthermore, the roles of three pharmacophores, a catechol moiety, a nitrile moiety, and acidic moieties, are discussed using in silico docking studies.

Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres by organocopper reagents and application to conformationally restricted cyclic RGD peptidomimetics.

Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres corresponding to dipeptides having one N-methylamino acid, and application to bioactive peptides, are described. In a key reaction introducing the chiral alpha-alkyl group of the isosteres, organocopper-mediated alkylation of syn-beta-methylated gamma-mesyloxy-alpha,beta-enoate 26a afforded E- and Z-isomers of anti-S(N)2' products in a solvent-dependent manner. The resulting two isosteres, D-Phe-psi[(E)-CH=CMe]-L-Val 27a and D-Phe-psi[(Z)-CH=CMe]-L-Val 28b, which corresponded to trans- and cis-conformers of D-Phe-L-MeVal, respectively, were utilized in a structure-activity relationship study on cyclic RGD peptides 1 and 2, in company with a psi[(E)-CH=CH]-type alkene dipeptide isostere, D-Phe-psi[(E)-CH=CH]-L-Val.

Regio- and stereoselective synthesis of (E)-alkene trans-Xaa-Pro dipeptide mimetics utilizing organocopper-mediated anti-S(N)2' reactions.

Proline dipeptides (Xaa-Pro) exist as an equilibrium mixture of cis- and trans-rotamers, which depends on the energy barriers for imide isomerization. This conformation mixture contributes to both structure and function of proline-containing peptides and proteins. Structural motifs resembling these cis- or trans-conformers have served as useful tools for elucidating contributions of proline residues in the physicochemical and biological profiles of structures which contain them.

Clarification of mechanism of human sputum elastase inhibition by a new inhibitor, ONO-5046, using electrospray ionization mass spectrometry.

Liquid chromatography electrospray ionization mass spectrometry (LC/ESI-MS) to probe the nature of the covalent E-I complex was successfully applied to clarify the mechanism of human sputum elastase (HSE) inhibition by a new inhibitor, ONO-5046. The mass spectrum of the four HSE isozymes displayed their molecular ion peaks at m/z=26,018, 25,929, 25,200, and 25,054, respectively. Immediately after incubation, inactivation of HSE with ONO-5046 increased the four molecular ion peaks by approximately 84 amu, which was assigned to the mass unit of the pivaloyl moiety of ONO-5046.

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.

Diastereoselective synthesis of psi[(E)-CMe=CH]- and psi[(E)-CMe=CMe]- type dipeptide isosteres based on organocopper-mediated anti-S(N)2' reaction.

[reaction: see text] A straightforward synthetic route for the synthesis of diastereomerically pure psi[(E)-CMe=CH]- and psi[(E)-CMe=CMe]-type dipeptide isosteres was developed on the basis of regio- and stereoselective anti-S(N)2' alkylation of 3-(N-Boc-5-methyl-4-substituted-oxazolidin-2-on-5-yl)acrylates with organocopper reagents.

Diastereoselective synthesis of psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type dipeptide isosteres by organocopper-mediated anti-S(N)2' reaction.

[reaction: see text] Acyclic psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type dipeptide isosteres were efficiently synthesized. In a key reaction, alpha-alkylation of gamma-mesyloxy-beta-methyl-alpha,beta-unsaturated esters with organocyanocuprates in diethyl ether or tetrahydrofuran preferentially afforded the psi[(E)-CH=CMe]- or psi[(Z)-CH=CMe]-isomer, respectively, via anti-S(N)2' mechanism.