期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 21, 页码 6897-6911出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm9012054
关键词
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资金
- NINDS and the Anticonvulsant Screening Program (ASP) at the National Institutes of Health
- National Institute of Netll-ological Disorders and Stroke [R01NS054112, F31NS060358]
- Korean Government (MOEHRD) [KRF-2006-352-C00042]
(R)-Lacosamide ((R)-2, (R)-N-benzyl 2-acetamido-3-methoxypropionamide) has recently gained regulatory approval for the treatment of partial-onset seizures in adults. Whole animal pharmacological studies have documented that (R)-2 function is unique: A robust strategy is advanced for the discovery of interacting proteins associated with function and toxicity of (R)-2 through the use of (R)-2 analogues, 3, which contain affinity bait (AB) and chemical reporter (CR) functional groups. In 3, covalent modification of the interacting proteins proceeds at the AB moiety, and detection or isolation of the selectively captured protein occurs through the bioorthogonal CR group upon reaction with all appropriate probe. We report the synthesis, pharmacological evaluation, and interrogation of the mouse soluble brain proteome using 3 where the AB group is an isothiocyanate moiety. One compound, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-9), exhibited excellent Seizure protection in mice, and like (R)-2, anticonvulsant activity principally resided in the (R)-stereoisomer. Several proteins were preferentially labeled by (R)-9 compared with (S)-9, including collapsin response mediator protein 2.
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