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Bioorg Med Chem. 2005 Jan 17;13(2):425-32.

Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphate.

Author information

1
Research Laboratory III (Immunology), Mitsubishi Pharma Corporation, Kamoshida-cho 1000, Aoba-ku, Yokohama 227-0033, Japan. kiuchi.masatoshi@ms.m-pharma.co.jp

Abstract

A practical asymmetric synthesis of both enantiomers of the immunosuppressive FTY720-phosphate (2) was accomplished, and the enantiomers were pharmacologically evaluated. Several lipases showed considerable activity and enantioselectivity for O-acylation of N-acetyl FTY720 (3) or N-benzyloxycarbonyl FTY720 (7) in combination with vinyl acetate or benzyl vinyl carbonate as the acyl donors. The synthesis using the lipase-catalyzed acylation as the key step produced the enantiomerically pure (>99.5% ee) enantiomers of 2 in multigram quantities. (S)-Isomer of 2 had more potent binding affinities to S1P(1,3,4,5) and inhibitory activity on lymphocyte migration toward S1P than (R)-2, suggesting that (S)-isomer of 2 is responsible for the immunosuppressive activity after administration of 1. Severe bradycardia was observed in anesthetized rats when (S)-2 was administered intravenously, while (R)-2 had no clear effect on heart rate up to 0.3 mg/kg.

PMID:
15598563
DOI:
10.1016/j.bmc.2004.10.008
[Indexed for MEDLINE]

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