Yumiko Mizuno

C-GLYCOSYLATED ARYL TINS: VERSATILE BUILDING BLOCKS FOR ARYL C-GLYCOSIDE GLYCOMIMETICS

ABSTRACT C-glycosylated aryl tins have been prepared as versatile building blocks of physiologically stable glycomimetics for glycoepitopes that have been recognized to serve biologically important roles in cell biochemistry.

C-Glycosylated Diphenylmethanes and Benzophenones: The Stille Coupling Reaction of C-Glycosylated Aryl Tins with Benzyl Bromides and Acid Chlorides

ABSTRACT C-glycosylated diphenylmethanes and C-glycosylated benzophenones were prepared by the palladium-catalyzed cross-coupling reaction of C-glycosylated aryl tins with various benzyl bromides or acid chlorides to provide physiologically stable glycomimetics of miscellaneous glycoepitopes.

Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist

S1P(3)-sparing S1P(1) agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC(50) value of 4.0 nM for human S1P(1) and over 5000-fold selectivity against S1P(3). The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID(50) value was determined at 0.407mg/kg. The docking studies of CS-2100 with the homology model of S1P(1) and S1P(3) showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P(3), not in the case of Leu276 in S1P(1). This observation gives an explanation for the excellent S1P(3)-sparing characteristic of CS-2100.

Synthesis and evaluation of CS-2100, a potent, orally active and S1P3- sparing S1P1 agonist

Modulators of sphingosine phosphate receptor-1 (S1P(1)) have recently been focused as a suppressant of autoimmunity. We have discovered a 4-ethylthiophene-based S1P(1) agonist 1-({4-Ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylic acid (CS-2100, 8) showing potent S1P(1) agonist activity against S1P(3) and an excellent in vivo potency. We report herein the synthesis of CS-2100 (8) and pharmacological effects such as S1P(1) and S1P(3) agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effects on adjuvant-induced arthritis and experimental autoimmune encephalomyelitis (EAE) in animal models. The pharmacokinetic data were also reported. CS-2100 (8) had >5000-fold greater agonist activity for human S1P(1) (EC(50); 4.0 nM) relative to S1P(3) (EC(50); >20,000 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-2100 (8) in rats, lymphocyte counts decreased significantly, with a nadir at 8 and/or 12 h post-dose and recovery to vehicle control levels by 24-48 h post-dose. CS-2100 (8) is efficacious in the adjuvant-induced arthritis model in rats (ID(50); 0.44 mg/kg). In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for 0.3 and 1 mg/kg CS-2100 (8) groups in mice. While CS-2100 (8) showed potent efficacy in various animal disease models, it was also revealed that the central 1,2,4-oxadiazole ring of CS-2100 (8) was decomposed by enterobacteria in intestine of rats and monkeys, implicating the latent concern about an external susceptibility in its metabolic process in the upcoming clinical studies.

C-Glycosylated Biphenyls: The Stille Coupling Reaction of C-Glycosylated Aryl Tins with Aryl Bromides

ABSTRACT C-glycosylated biphenyls were prepared by the palladium-mediated cross-coupling reaction of C-glycosylated aryl tins with variously substituted aryl bromides, which will provide physiologically stable glycomimetics of various glycoepitopes. A C-sialylated biphenyl, a glycomimetic of biologically significant sialosides, is also available by this method.

Synthesis and SAR of 1,3-thiazolyl thiophene and pyridine derivatives as potent, orally active and S1P3-sparing S1P1 agonists

We have previously disclosed 1,2,4-oxadiazole derivative 3 as a potent S1P(3)-sparing S1P(1) agonist. Although compound 3 exhibits potent and manageable immunosuppressive efficacy in various in vivo models, recent studies have revealed that its 1,2,4-oxadiazole ring is subjected to enterobacterial decomposition. As provisions for unpredictable issues, a series of alternative compounds were synthesized on the basis of compound 3. Extensive SAR studies led to the finding of 1,3-thiazole 24c with the EC(50) value of 3.4 nM for human S1P(1), and over 5800-fold selectivity against S1P(3). In rat on host versus graft reaction (HvGR), the ID(50) value of 24c was determined at 0.07 mg/kg. The pharmacokinetics in rat and monkey is also reported. Compared to compound 3, 24c showed excellent stability against enterobacteria.

Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists

We report herein the synthesis and structure-activity relationships (SAR) of a series of benzyl ether compounds as an S1P₁ receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P₁ and S1P₃ agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P₁/S1P₃ selectivity. These changes of the S1P₁ and S1P₃ agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P₁ X-ray crystal structure and S1P₃ homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P₁/S1P₃ selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats.