Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist
| Autor: | Hiroshi Yuita, Reina Kaneko, Masayoshi Asano, Takashi Kagari, Takaichi Shimozato, Nobuaki Watanabe, Takahide Nishi, Hiromi Doi, Wataru Tomisato, Takako Kimura, Yumiko Mizuno, Yumi Kawase, Yasuyuki Abe, Miyuki Nagasaki, Yukiko Sekiguchi, Futoshi Nara, Keiko Oguchi-Oshima, Ryotaku Inoue, Tsuyoshi Nakamura, Kazuhiko Tamaki |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Agonist medicine.drug_class Stereochemistry Clinical Biochemistry Administration Oral Pharmaceutical Science Thiophenes Pharmacology Binding Competitive Biochemistry Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound In vivo Drug Discovery medicine Thiophene Animals Humans Homology modeling Molecular Biology Graft reaction Oxadiazoles Molecular Structure Chemistry Organic Chemistry Rats Receptors Lysosphingolipid Orally active Docking (molecular) Immune System Molecular Medicine Immunosuppressive Agents |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:1788-1792 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2011.12.019 |
| Popis: | S1P(3)-sparing S1P(1) agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC(50) value of 4.0 nM for human S1P(1) and over 5000-fold selectivity against S1P(3). The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID(50) value was determined at 0.407mg/kg. The docking studies of CS-2100 with the homology model of S1P(1) and S1P(3) showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P(3), not in the case of Leu276 in S1P(1). This observation gives an explanation for the excellent S1P(3)-sparing characteristic of CS-2100. |
| Databáze: | OpenAIRE |
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