Part 2: Design, synthesis and evaluation of hydroxyproline-derived α 2δ ligands

A series of proline-derived α 2δ ligands has been designed through cyclisation of a lead series of N-alkylated glycines. Excellent levels of potency have been achieved and compound 18 has been progressed to clinical development. Conformational constraint has been used to design a potent series of α...

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Bibliographic Details
Published inBioorganic & medicinal chemistry letters Vol. 21; no. 12; pp. 3767 - 3770
Main Authors Rawson, David J., Brugier, Delphine, Harrison, Anthony, Hough, Jo, Newman, Julie, Otterburn, Joe, Maw, Graham N., Price, Jenny, Thompson, Lisa R., Turnpenny, Paul, Warren, Andrew N.
Format Journal Article
LanguageEnglish
Published Elsevier Ltd 15.06.2011
Subjects
Gabapentin
Glomerular filtration
Renal clearance
α 2δ
Glomerular filtration
Gabapentin
Renal clearance
α 2δ
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Summary:A series of proline-derived α 2δ ligands has been designed through cyclisation of a lead series of N-alkylated glycines. Excellent levels of potency have been achieved and compound 18 has been progressed to clinical development. Conformational constraint has been used to design a potent series of α 2δ ligands derived from the readily available starting material (2 S,4 R)-hydroxy- l-proline. The ligands have improved physicochemistry and potency compared to their linear counterparts (described in our earlier publication) and the lead compound has been progressed to clinical development.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.04.056