BIOMAT Database Logo BIOMAT Database Logo

Synthesis and biological evaluation of novel 9-substituted-8-hydroxyadenine derivatives as potent interferon inducers. 2006

Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
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

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.

UI MeSH Term Description Entries
D007369 Interferon Inducers Agents that promote the production and release of interferons. They include mitogens, lipopolysaccharides, and the synthetic polymers Poly A-U and Poly I-C. Viruses, bacteria, and protozoa have been also known to induce interferons. Inducers, Interferon
D007372 Interferons Proteins secreted by vertebrate cells in response to a wide variety of inducers. They confer resistance against many different viruses, inhibit proliferation of normal and malignant cells, impede multiplication of intracellular parasites, enhance macrophage and granulocyte phagocytosis, augment natural killer cell activity, and show several other immunomodulatory functions. Interferon
D008252 Macaca fascicularis A species of the genus MACACA which typically lives near the coast in tidal creeks and mangrove swamps primarily on the islands of the Malay peninsula. Burmese Long-Tailed Macaque,Crab-Eating Monkey,Cynomolgus Monkey,M. f. aurea,M. fascicularis,Macaca fascicularis aurea,Monkey, Crab-Eating,Monkey, Cynomolgus,Crab-Eating Macaque,Burmese Long Tailed Macaque,Crab Eating Macaque,Crab Eating Monkey,Crab-Eating Macaques,Crab-Eating Monkeys,Cynomolgus Monkeys,Long-Tailed Macaque, Burmese,Macaque, Burmese Long-Tailed,Macaque, Crab-Eating,Monkey, Crab Eating
D008297 Male Males
D011725 Pyridines Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
D005289 Ferrets Semidomesticated variety of European polecat much used for hunting RODENTS and/or RABBITS and as a laboratory animal. It is in the subfamily Mustelinae, family MUSTELIDAE. Domestic Polecat,Domestic Polecats,European Polecat,European Polecats,Ferret,Mustela putorius,Mustela putorius furo,Polecat, Domestic,Polecat, European,Polecats, Domestic,Polecats, European
D000225 Adenine A purine base and a fundamental unit of ADENINE NUCLEOTIDES. Vitamin B 4,4, Vitamin B,B 4, Vitamin
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013154 Spleen An encapsulated lymphatic organ through which venous blood filters.

Related Publications

Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
Synthesis and biological evaluation of 2,8-disubstituted 9-benzyladenines: discovery of 8-mercaptoadenines as potent interferon-inducers.
July 2003, Bioorganic & medicinal chemistry,
Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
Design, synthesis and biological evaluation of some novel quinazolinone derivatives as potent apoptotic inducers.
May 2018, Future medicinal chemistry,
Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
Design, synthesis, and biological evaluation of N-arylpiperazine derivatives as interferon inducers.
December 2020, Bioorganic & medicinal chemistry letters,
Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
Synthesis and biological evaluation of N-phosphoryl dipeptide derivatives as potent apoptosis inducers.
January 2008, Protein and peptide letters,
Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
Synthesis and biological evaluation of 9-substituted tetracycline derivatives.
August 2002, Bioorganic & medicinal chemistry letters,
Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
Design, synthesis and biological evaluation of novel substituted benzoylguanidine derivatives as potent Na+/H+ exchanger inhibitors.
June 2009, Bioorganic & medicinal chemistry letters,
Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
Design, synthesis and biological evaluation of some novel sulfonamide derivatives as apoptosis inducers.
July 2017, European journal of medicinal chemistry,
Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
Synthesis and biological evaluation of novel benzyl-substituted (S)-phenylalanine derivatives as potent dipeptidyl peptidase 4 inhibitors.
September 2013, Bioorganic & medicinal chemistry,
Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
Synthesis and biological evaluation of novel 8- substituted sampangine derivatives as potent inhibitor of Zn2+-Aβ complex mediated toxicity, oxidative stress and inflammation.
April 2021, Bioorganic chemistry,
Yoshiaki Isobe, and Ayumu Kurimoto, and Masanori Tobe, and Kazuki Hashimoto, and Tomoaki Nakamura, and Kei Norimura, and Haruhisa Ogita, and Haruo Takaku
Study on Synthesis and Biological Evaluation of 3-Aryl Substituted Xanthone Derivatives as Novel and Potent Tyrosinase Inhibitors.
November 2019, Chemical & pharmaceutical bulletin,
Copied contents to your clipboard!