Systemic administration of a Toll-like receptor 7 (TLR7) agonist is effective to in suppressing Th2 derived inflammation, however systemic induction of various cytokines such as IL-6, IL-12, and type I interferon (IFN) is observed. This cytokine induction would be expected to cause flu-like symptoms. We have previously reported adenine compounds (3, 4) as interferon inducing agents acting as TLR7 agonists. To identify potent anti-inflammatory compounds without systemic side effects, a labile carboxylic ester as an antedrug functionality onto the N(9)-benzyl group of the adenine was introduced. We found that 9e was a potent TLR7 agonist (EC(50) 50 nM) and rapidly metabolized by human plasma (T(1/2) 2.6 min) to the pharmacologically much less active carboxylic acid 16. Intratracheal administration of 9e effectively inhibited allergen-induced airway inflammation without inducing cytokines systemically. Therefore, the TLR7 agonist with antedrug characteristics 9e (SM-324405) is a novel candidate for immunotherapy of allergic diseases.

Recently we reported the adenine derivatives 3a-d as novel interferon (IFN) inducers. In the present study, we conducted a detailed structure-activity relationship study of analogues of 3a-d with respect to their IFN-inducing activity, mainly focusing on the N(9)-position of the adenine. From this study, we found that introduction of the 3-pyridylmethyl moiety was effective to increase in vitro activity, and compound 9ae was identified as being the most potent IFN inducer. This compound gave a minimum effective concentration (MEC) of 3 nM, which is comparable with that of R-848, a second generation IFN inducer. Compound 9ae also demonstrated potent IFN-inducing activity at a dose of 0.1 mg/kg by oral administration in mice. Furthermore, compound 9ae induced IFN in monkeys in a dose dependent manner, with a potency superior to that of R-848. In addition, 9ae did not cause emesis in ferrets even at a dose of 30 mg/kg. In this study the maximum plasma concentration of 9ae was 1019 ng/mL (ca. 3.1 microM), which was approximately 1000-fold higher than the MEC value. Therefore, with respect to both the efficacy and the safety margin, compound 9ae (SM-276001) is considered to be a promising compound as an orally active IFN inducer.

1-o-Substituted phenylethanols gave diastereoselective ruthenium Cp complexes via coordination of ruthenium with benzylic oxygen. This reaction can be further applied to the diastereoselective ruthenium complexation of δ-lactone-bridged biaryls possessing a chiral benzyl alcohol function at the side chain. Although δ-lactone-bridged biphenyls 10a and 10b exist as an inseparable equilibrated atropisomeric mixture, the corresponding ruthenium complexes 11a and 11b were obtained as a single compound, respectively, with differentiated arene face complexation and fixation of the central bond. Analogous biaryl compound 15 with a naphthalene fragment gave three Cp ruthenium complexes, 16, 17, and 18, in various ratios depending on reaction temperature. Naphthalene ring-coordinated ruthenium complex 16 was isomerized to the complex 17 via axial isomerization and ruthenium fragment migration to the inverted arene face by heating at 50°C in dichloroethane, and the ruthenium complexes 16 and 17 were further transformed to benzene ring-coordinated ruthenium complex 18 by heating at 90°C. The diastereoselective ruthenium complexation with fixation (and isomerization) of the axial bond of δ-lactone-bridged biaryls 10 and 15 was supported by ab initio calculations. Also, the ab initio calculations of δ-lactone-bridged biaryl ruthenium complexes with a naphthalene fragment were well consistent with the experimental results. The obtained ruthenium complexes of δ-lactone-bridged biaryls afforded axially chiral biaryls by ring opening of δ-lactone with nonchiral reagents.