Transdermal administration of aqueous pregabalin solution as a potential treatment option for patients with neuropathic pain to avoid central nervous system-mediated side effects.

Pregabalin, (S)-3-isobutyl-γ-aminobutyric acid (GABA), is a widely used adjuvant therapy for patients with neuropathic pain, which is defined as chronic pain caused by lesions or diseases of the somatosensory nervous system. However, dizziness and somnolence (sleepiness) are common dose-limiting side effects, probably due to excessive sedative effects on higher centers of the central nervous system (CNS) which are involved in the anticonvulsant and analgesic actions of pregabalin. We speculated that transdermal delivery would minimize centrally mediated side effects.

Functionalized oxatriquinanes and their structural equilibrium in protic solvent.

We synthesized oxatriquinane hexafluorophosphate bearing an ethoxycarbonylmethyl group 7 or a 2-oxopropyl group 11. Both of these organic oxonium cation compounds were obtained as stable solids. However, (1)H-NMR analysis showed that oxatriquinane 7 was present as the oxonium cation in aprotic solvent CD₃CN, but was in rapid equilibrium with ring-opened bicyclic compound 8 in protic solvent CD₃OD.

Silicon-containing GABA derivatives, silagaba compounds, as orally effective agents for treating neuropathic pain without central-nervous-system-related side effects.

Neuropathic pain is a chronic condition resulting from neuronal damage. Pregabalin, the (S)-isomer of 3-isobutyl-γ-aminobutyric acid (GABA), is widely used to treat neuropathic pain, despite the occurrence of central nervous system (CNS)-related side effects such as dizziness and somnolence. Here we describe the pharmacology of novel GABA derivatives containing silicon-carbon bonds, silagaba compounds.

Synthesis of Am80 (tamibarotene) prodrug candidates, congeners and metabolites.

Compound 1 (IT-M-07000) was previously reported as a candidate prodrug of Am80 (Tamibarotene; used to treat acute promyelocytic leukemia), and shown to be efficiently metabolized to Am80 via β-oxidation. Here, we describe in detail the synthesis of 1, together with another tetradeuterated candidate prodrug, IT-YA-00616 (2), as well as two congeners, and several metabolic intermediates of 1 previously detected in mouse plasma.

Deprotonation equilibrium of 5-tropolonediazonium salt strongly favors 1,2,5-tropoquinone-5-diazide structure in certain solvents.

5-Tropolonediazonium salt 1 is a well-known intermediate for the preparation of 5-substituted tropolone derivatives, but 1,2,5-tropoquinone-5-diazide 2, which is expected to be formed by deprotonation of 1, has not been reported. We synthesized 2, and the structures of 1 and 2 were investigated and compared. NMR and UV spectral data indicated that 1 is easily deprotonated in water, methanol, DMSO, and DMF and exists in the form of 2 in these solvents (but not in acetone or acetonitrile) because of its strong acidity (estimated pKa -2.

Design, synthesis and evaluation of retinoids with novel bulky hydrophobic partial structures.

Many synthetic retinoids contain an aromatic structure with a bulky hydrophobic fragment. In order to obtain retinoids with therapeutic potential that do not bind to or activate retinoic acid X receptors (RXRs), we focused on the introduction of novel hydrophobic moieties, that is, metacyclophane, phenalene and benzoheptalene derivatives. The designed compounds were synthesized and their agonistic activities towards RARs and RXRs were evaluated.

(R)- and (S)-4-Amino-3-(trimethylsilyl)methylbutanoic acids ameliorate neuropathic pain without central nervous system-related side effects.

Neuropathic pain is a chronic pain condition resulting from neuronal damage, and is usually treated with pregabalin or gabapentin, which are structurally related to γ-aminobutyric acid (GABA) and are originally developed as anticonvulsant drugs. Here, we report the synthesis and pharmacology of (R)- and (S)-4-amino-3-(trimethylsilyl)methylbutanoic acids (1a and 1b), which showed analgesic activity as potent as that of pregabalin in the Chung spinal nerve ligation model. However, unlike pregabalin, 1a and 1b do not have antiepileptic effects, and they are therefore promising candidates for selective therapeutic agents to treat neuropathic pain without central nervous system-related side effects.

Novel synthesis of ureas: application of t-butylureas.

Otherwise inaccessible tropolonylureas were prepared by reaction of t-butylurea with appropriate amines, with elimination of t-butylamine. This method is also generally applicable for urea synthesis.

Disposition of a new tamibarotene prodrug in mice.

Recently, a new compound IT-M-07000 was designed as a prodrug of tamibarotene, one of the therapeutic agents for acute promyelocytic leukemia. In the present study, IT-M-07000 was administered to mice to investigate whether it is actually metabolized to tamibarotene. Its metabolic pathway and the utility as a tamibarotene prodrug were also evaluated.

On the structure of "5-nitrosotropolone".

It has long been discussed whether "5-nitrosotropolone" 1 takes the nitroso structure 1A or the tautomeric oxime structure 1B. Analysis of NMR and UV spectra data in this study indicates that the tropoquinone-5-monoxime 1B is preferred. The UV absorption shift to longer wavelength at dilute solutions is attributable to the dissociated form 3.