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An oral S1P1 antagonist prodrug with efficacy in vivo: discovery, synthesis and evaluation

Angst, Daniela, Bollbuck, Birgit, Janser, Philipp, Quancard, Jean, Buehlmayer, Peter, Berst, Frederic, Oberer, Lukas, Beerli, Christian, Pally, Charles, Streiff, Markus and Bassilana, Frederic (2012) An oral S1P1 antagonist prodrug with efficacy in vivo: discovery, synthesis and evaluation. Journal of Medicinal Chemistry, 55 (22). pp. 9722-9734. ISSN 0022-2623


A prodrug approach to optimize the oral exposure of an S1P1 antagonist for chronic efficacy studies led to the discovery of (S)-2-{[3'-(4-Chloro-2,5-dimethyl-benzenesulfonylamino)-3,5-dimethyl-biphenyl-4-carbonyl]-methyl-amino}-4-dimethylamino-butyric acid methyl ester (BVM924). Due to the steric hindrance and the partial double bond character of the amide group and the resulting large rotational barrier around the amide bond two conformers of (BVM924) can be detected in solution and their equilibration was investigated by UPLC and 1H NMR. Methyl ester prodrug (BVM924) is hydrolyzed in vivo to the corresponding carboxylic acid (BVS819), a potent and selective S1P1 antagonist. Oral administration of the prodrug (BVM924) induces sustained peripheral lymphocyte depletion in rats. In a rat cardiac transplantation model co-administration of a nonefficacious dose of prodrug (BVM924) with a nonefficacious dose of sotrastaurin (AEB071), a protein kinase C inhibitor, or everolimus (RAD001), an mTOR inhibitor, effectively prolonged the survival time of rat cardiac allografts. This demonstrates that clinically useful immunomodulation mediated by the S1P1 receptor can be achieved with an S1P1 antagonist generated in vivo after oral administration of its prodrug.

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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14