Synthesis and Biological Evaluation of Novel 9-Substituted-8-Hydroxyadenine Derivatives as Potent Interferon Inducers

Abstract

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.

Toll-Like Receptor-7 Agonist Decoration Enhances the Adjuvanticity of Chitosan–DNA Nanoparticles

“…Synthesis of Boc–NH–PEG–HA was achieved according to Isobe et al14 with some modifications. First, 22.97 mg (83.3 µmol, five times excess of free amines) of CHA were dissolved in 20 mL n ‐butanol at 120°C followed by the addition of 50 mg (16.7 µmol) of Boc–NH–PEG–NH 2 .…”

Structural requirements for TLR7-selective signaling by 9-(4-piperidinylalkyl)-8-oxoadenine derivatives

“…The few reported oxoadenines with cycloalkyl groups attached to the nitrogen at the 9-position (directly or via a methylene unit) have demonstrated weak or diminished IFN induction. 7,11 Since alkyl linker length on the corresponding N1 of 1-phenylalkylimidazoquinolines is known to profoundly effect IFN-inducing activity, 6 we were particularly interested in the synthesis and biological evaluation of a series of 4-piperidinylalkyl derivatives of 2 in which the length of the N9 alkyl linker was systematically varied (compounds 3a–g , Figure 1). In addition to the ability to form water-soluble salts, the 4-piperidinyl moiety of oxoadenines 3a–g also provides a suitable handle for potential N-derivatization and conjugation as substitution of the aromatic amino group in both the oxoadenine and imidazoquinoline series abolishes IFN-inducing activity.…”

Pharmacokinetic-Pharmacodynamic Modeling of Alpha Interferon Response Induced by a Toll-Like 7 Receptor Agonist in Mice

“…All samples were analyzed for BHMA quantification by using a PE-Sciex API 4000 (Turbo V Ionspray source) quadrupole mass spectrometer. Samples (180 l) were injected with the use of a PAL autosampler (CTC Analytics, Zwingen, Switzerland) onto a C 18 Opti-Lynx 15-by 2.1-mm, 40-m-particle-size column (Optimize Technologies). The total run time was 2 min.…”

“…The need to develop more available, better-tolerated, and more effective medicines is therefore clear. To this end, one of the areas of interest has been the targeting of IFN inducers (13,18) and specifically Toll-like 7 receptor (TLR-7) agonists (9). The TLR family plays a critical role in the innate immune response via recognition of pathogen-associated molecular patterns (PAMPs).…”