Synthesis and biological evaluation of novel 9-substituted-8-hydroxyadenine derivatives as potent interferon inducers.
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.
Chemistry Research Laboratories and Discovery Research Laboratories II, Dainippon Sumitomo Pharmaceuticals Company Ltd., 1-98, Kasugade Naka, 3-chome, Konohana-ku, Osaka 554-0022, Japan. yoshiaki-isobe@ds-pharm.co.jp
Yoshiaki
Y
Isobe
Ayumu
A
Kurimoto
Masanori
M
Tobe
Kazuki
K
Hashimoto
Tomoaki
T
Nakamura
Kei
K
Norimura
Haruhisa
H
Ogita
Haruo
H
Takaku
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D005289:Ferrets; D066298:In Vitro Techniques; D007369:Interferon Inducers / Q000138:chemical synthesis* / Q000494:pharmacology; D007372:Interferons / Q000096:biosynthesis; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced
C509861:2-butylamino-8-hydroxy-9-(6-methylpyridine-3-ylmethyl)adenine; D007369:Interferon Inducers; D011725:Pyridines; D007372:Interferons; D000225:Adenine