Tamio Sugawara

A novel chemical delivery system for brain targeting.

Two different chemical approaches for brain drug delivery and targeting are proposed in the present review. One is a chemical drug delivery using a ring-closure reaction to the hydrophilic quaternary thiazolium compound in the brain. The other is a chemical drug targeting utilizing the nutrient receptor (transporter) system on the blood-brain barrier. The brain delivery system has been optimized and it was demonstrated that the brain delivery of three drugs, a drug for Parkinsons disease, an excitatory amino acid antagonist and a free radical scavenger, were improved by the conjugation with cis-2-formylaminoethenylthio derivatives in vivo. As for the brain targeting system, it was demonstrated that the conjugation with L-Glu improved the drugs brain distribution via the L-Glu excitatory and/or transport receptors in vitro and in vivo. These findings suggest that the concepts of two chemical approaches will contribute to the development of new central nervous system drugs.

Synthesis of a trisaccharide component of the capsular polysaccharide of Streptococcus pneumoniae type 19F

2-O-[4-O-(2-Acetamido-2-deoxy-beta-D-mannopyranosyl)-alpha-D- glucopyranosyl]-alpha,beta-L-rhamnopyranose, a structural component of the capsular polysaccharide of Streptococcus pneumoniae type 19F, has been synthesized by sequential glycosylation reactions using the glycosyl acceptor 2,2,2-trichloroethyl 3,4-di-O-benzyl-alpha-L-rhamnopyranoside (prepared from the known 2-O-acetyl-3,4-di-O-benzyl-alpha-L-rhamnopyranosyl chloride), and the glycosyl donors 4-O-acetyl-2,3,6-tri-O-benzyl-alpha-D-glucopyranosyl chloride and 4,6-di-O-acetyl-2-azido-3-O-benzyl-2-deoxy-alpha-D-mannopyranosyl bromide (prepared in seven steps from the known methyl 2-azido-4,6-O-benzylidene-2-deoxy-alpha-D-altropyranoside). The corresponding 8-(methoxycarbonyl)octyl glycoside has also been synthesized, by coupling of 8-(methoxycarbonyl)octyl trifluoromethanesulfonate and the sodium salt of 2-O-[4-O-(2-acetamido-4,6-di-O-acetyl-3-O-benzyl-2-deoxy-beta-D- mannopyranosyl)-2,3,6-tri-O-benzyl-alpha-D-glucopyranosyl]-3,4-di-O- benzyl-alpha,beta-L-rhamnopyranose.

An efficient, stereoselective synthesis of 4-E- and 4-Z-d-erythro-sphingenine and related compounds from 2-amino-2-deoxy-d-glucose

Efficient, stereoselective synthesis of 4-E- and 4-Z-D-erythro-sphingenines having C16, C18, and C20 carbon-chains was achieved in 13 steps, starting from allyl 2-benzyloxycarbonylamino-2-deoxy-alpha-D-glucopyranoside. 2-Amino-1,6-di-O-tert- butyldiphenylsilyl-2-N,3-O-carbonyl-2-deoxy-D -allitol was used as the key intermediate.

Synthesis of ω-(methoxycarbonyl)alkyl and 9-(methoxycarbonyl)-3,6-dioxanonyl glycopyranosides for the preparation of carbohydrate-protein conjugates

omega-(Methoxycarbonyl)alkyl glycopyranosides of D-mannose having C4, C7, C9, C12, and C15 carbon chains, L-fucose and 2-acetamido-2-deoxy-D-mannose having C7 and C9 carbon chains, D-xylose and 2-acetamido-2-deoxy-L-fucose having a C9 carbon chain, and 9-(methoxycarbonyl)-3,6-dioxanonyl glycopyranosides of D-mannose, 2-acetamido-2-deoxy-D-mannose, and L-fucose were synthesized as intermediates for coupling to human serum albumin in order to examine the effect of chain length and hydrophobicity of the spacer arm on the binding specificity of lectins. 8-(Methoxycarbonyl)octyl glycosides of beta-D-Man-(1----2)-alpha-D-Man, alpha-D-Man-(1----2)-alpha-D-Man, alpha-D-ManNAc-(1----2)-alpha-D-Man, beta-D-GlcNAc-(1----2)-alpha-D-Man, and their 6-O-positional isomers, beta-D-Man-(1----6)-alpha-D-Man, alpha-D-Man-(1----6)-alpha-D-Man, alpha-D-ManNAc-(1----6)-alpha-D-Man, and beta-D-GlcNAc-(1----6)-alpha-D-Man, were also synthesized.

Conjugation with l-glutamate for in vivo brain drug delivery

In vitro studies have shown that conjugation of a model compound [p-di(hydroxye-thyl)-amino-D-phenylalanine (D-MOD)] with L-Glu can improve D-MOD permeation through the bovine brain microvessel endothelial cell monolayers (Sakaeda et al., 2000). The transport of this D-MOD-L-Glu conjugate is facilitated by the L-Glu transport system. In this paper, we evaluate the in vivo brain delivery of model compounds (i.e. D-MOD, p-nitro-D-phenylalanine (p-nitro-D-Phe), 5, 7-dichlorokynurenic acid (DCKA) and D-kyotor-phin) and their L-Glu conjugates. DCKA was also conjugated with L-Asp and L-Gln amino acids. The analgesic activities of D-kyotorphin and its L-Glu conjugate were also evaluated. The results showed that the brain-to-plasma concentration ratio of D-MOD-L-Glu was higher than the D-MOD alone; however, the plasma concentration of both compounds were the same. The plasma concentration of p-nitro-D-Phe-L-Glu conjugate was higher than the parent p-nitro-D-Phe; however, the brain-to-plasma concentration ratio of p-nitro-D-Phe was higher than its conjugate. On the other hand, both DCKA and DCKA conjugates have a low brain-to-plasma concentration ratio due to their inability to cross the blood-brain barrier (BBB). The L-Asp and L-Glu conjugates of DCKA have elevated plasma concentrations relative to DCKA; however, the DCKA-L-Gln conjugate has the same plasma concentration as DCKA. For D-kyotorphin, both the parent and the L-Glu conjugate showed similar analgesic activity. In conclusion, conjugation of a non-permeable drug with L-Glu may improve the drugs brain delivery; however, this improvement may depend on the physicochemical and receptor binding properties of the conjugate.

Novel synthesis of 1- and 3-epi-tobramycin and 1-epi-kanamycin A

Abstract Electrochemical reduction of 1-deamino-3,2′,6′,3″-tetra- N -formyl-1-hydroxyiminotobramycin ( 4 ) and 1-deamino-3,6′,3″-tri- N -formyl-1-hydroxyiminokanamycin A ( 5 ) (prepared in good yields by oxidation of the corresponding amines with hydrogen peroxide in the presence of a catalytic amount of sodium tungstate), by using a mercury cathode at −1.85 volt ( vs . a saturated calomel electrode) gave principally 1- epi -tobramycin ( 6 ) and -kanamycin A ( 7 ) derivatives. Similar results were obtained by catalytic hydrogenation of 4 and 5 over Raney nickel. The electrochemical reduction or catalytic hydrogenation of 3-deamino-1,2′,6′,3″-tetra- N -formyl-3-hydroxyiminotobramycin ( 17 ) gave mainly the corresponding tobramycin derivative. Reduction of 4 and 17 with sodium cyanoborohydride gave principally the corresponding 1- epi -1- and 3- epi -3-hydroxyamino derivatives. Hydrogenation of these over Raney nickel gave the corresponding amines in quantitative yields. Hydrolysis of 1- and 3- epi -tobramycins with 48% hydrobromic acid under reflux gave (1 l -1,3, 4 2 ,6-4,6-diaminocyclohexanetriol, [α] 21.5 D +39.4° and (1 d )-1,3, 4 2 ,6-4,6-diaminocyclohexanetriol, [α] 24 D −37.0°, respectively.

Synthesis of 8-aminooctyl glycopyranosides and of their conjugates with poly(l-glutamic acid) having a 2-(4-hydroxyphenyl) ethylamino group for radiolabeling

Abstract 8-Aminooctyl glycopyranosides of β- d -galactose, β- l -fucose, α- and β- d -xyloses, α- and β- d -mannoses, 2-acetamido-2-deoxy-β- d -mannose, and 2-acetamido-2-deoxy-α- l -fucose were synthesized under Koenigs-Knorr type glycosylation reaction conditions using the corresponding glycopyranosyl halides or 2-azido-2-deoxy-glycopyranosyl halides and N-(8-hydroxyoctyl) phthalimide. Condensation of 8-aminooctyl glycopyranosides of β- d -galactose, β- l -fucose, α- d -xylose, and α- and β- d -mannoses with poly( l -glutamic acid) in the presence of 4-(2-aminoethyl)phenol and 1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline as a condensation reagent, gave [8-(β- d -galactopyranosyloxy) octylamine]36-[2-(4-hydroxyphenyl)ethylamine]3-poly( l -glutamic acid) conjugate (41), [8-(β- l -fucopyranosyloxy)octylamine], 16-[2-(4-hydroxyphenyl)ethylamine]4-poly( l -glutamic acid) conjugate (42), [8-(α- d -xylopyranosyloxy)octylamine]12-[2-(4-hydroxyphenyl)ethylamine]2-poly( l -glutamic acid) conjugate (43), [8-(α- d -mannopyranosyloxy)octylamine]18-[2-(4-hydroxyphenyl)ethylamine]5-poly( l -glutamic acid) conjugate (44), and [8-(β- d -mannopyranosyloxy)octylamine]27-[2-(4-hydroxyphenyl)ethylamine]2-poly( l -glutamic acid) conjugate (45), respectively. The plasma elimination rates of [125I]-labeled carbohydrate- poly( l -glutamic acid) conjugates bearing 8-(β- d -galactopyranosyloxy)octylami 8-(α- d -mannopyranosyloxy)octylamino residues (41 and 45) after intravenous administration to rats were more rapid than that of [125I] [2-(4-hydroxy-phenyl)ethylamine]5-poly( l -glutamic acid) conjugate (40).

Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate)

We have explored orally effective thyrotropin-releasing hormone (TRH) mimetics, showing oral bioavailability and brain penetration by structure–activity relationship (SAR) study on the basis of in vivo antagonistic activity on reserpine-induced hypothermia in mice. By primary screening of the synthesized TRH mimetics, we found a novel TRH mimetic: l-pyroglutamyl-[3-(thiazol-4-yl)-l-alanyl]-l-prolinamide with a high central nervous system effect compared with TRH as a lead compound. Further SAR optimization studies of this lead compound led to discovery of a novel orally effective TRH mimetic: 1-{N-[(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine trihydrate (rovatirelin hydrate), which was selected as a candidate for clinical trials.