Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist.

Autor: Nakamura T; Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan., Asano M, Sekiguchi Y, Mizuno Y, Tamaki K, Kimura T, Nara F, Kawase Y, Shimozato T, Doi H, Kagari T, Tomisato W, Inoue R, Nagasaki M, Yuita H, Oguchi-Oshima K, Kaneko R, Watanabe N, Abe Y, Nishi T
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Feb 15; Vol. 22 (4), pp. 1788-92. Date of Electronic Publication: 2012 Jan 02.
DOI: 10.1016/j.bmcl.2011.12.019
Abstrakt: 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.
(Copyright © 2011 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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