- Proteomic searches comparing two (R)-lacosamide affinity baits: An electrophilic arylisothiocyanate and a photoactivated arylazide group
-
We have advanced a novel strategy to search for lacosamide ((R)-1) targets in the brain proteome where protein binding is expected to be modest. Our approach used lacosamide agents containing "affinity bait" (AB) and "chemical reporter" (CR) units. The affinity bait moiety is designed to irreversibly react with the target, and the CR group permits protein detection and capture. In this study, we report the preparation and evaluation of (R)-N-(4-azido)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-3) and show that this compound exhibits potent anticonvulsant activities in the MES seizure model in rodents. We compared the utility of (R)-3 with its isostere, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-2), in proteomic studies designed to identify potential (R)-1 targets. We showed that despite the two-fold improved anticonvulsant activity of (R)-3 compared with (R)-2, (R)-2 was superior in revealing potential binding targets in the mouse brain soluble proteome. The difference in these agents' utility has been attributed to the reactivity of the affinity baits (i.e., (R)-2: aryl isothiocyanate moiety; (R)-3: photoactivated aryl azide intermediates) in the irreversible protein modification step, and we conclude that this factor is a critical determinant of successful target detection where ligand (drug) binding is modest. The utility of (R)-2 and (R)-3 in in situ proteome studies is explored.
- Park, Ki Duk,Stables, James P.,Liu, Rihe,Kohn, Harold
-
scheme or table
p. 2803 - 2813
(2010/08/21)
-
- Lacosamide isothiocyanate-based agents: Novel agents to target and identify lacosamide receptors
-
(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 an 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. 2009 American Chemical Society.
- Ki, Duk Park,Morieux, Pierre,Salomé, Christophe,Cotten, Steven W.,Reamtong, Onrapak,Eyers, Claire,Gaskell, Simon J.,Stables, James P.,Liu, Rihe,Kohn, Harold
-
supporting information; experimental part
p. 6897 - 6911
(2010/04/24)
-
- NOVEL N-BENZYLAMIDE SUBSTITUTED DERIVATIVES OF 2-(ACYLAMIDO)ACETIC ACID AND 2-(ACYLAMIDO)PROPIONIC ACIDS: POTENT NEUROLOGICAL AGENTS
-
A first aspect of the invention is a compound (sometimes also referred to herein as an "active agent" or "active compound") of Formula (I) or ( Ia): or a pharmaceutically acceptable salt or prodrug thereof. Compositions thereof and methods of using the same (e.g. for the treatment of a neurological disease) are also described.
- -
-
Page/Page column 28-29
(2009/12/27)
-
- Stereochemistry of Nucleophilic Ring-Opening Reactions of Optically Active N-Acetyl-2-Methoxycarbonylaziridine.
-
The SN2-like mechanism of the nucleophilic attack of sodium azide on (S)-(-)-N-acetyl-2-methoxycarbonylaziridine was verified through the chemical correlation of the ring-opening products with (S)-(+)- or (R)-(-)-2,3-diaminopropanoic acid monohydrochloride.
- Davoli, Paolo,Forni, Arrigo,Moretti, Irene,Prati, Fabio
-
p. 2011 - 2016
(2007/10/03)
-
- Candida cylindracea Lipase-Catalysed Hydrolysis of Methyl Aziridine-2-carboxylates and 2,3-dicarboxylates
-
N-Substituted aziridine-2-carboxylates and 2,3-dicarboxylates have been resolved with good to excellent stereochemical purity by enzymatic hydrolysis catalysed by lipase from Candida cylindracea.
- Bucciarelli, Maria,Forni, Arrigo,Moretti, Irene,Prati, Fabio,Torre, Giovanni
-
p. 3041 - 3046
(2007/10/02)
-