Part 2: Design, synthesis and evaluation of hydroxyproline-derived α2δ ligands

Conformational constraint has been used to design a potent series of α2δ ligands derived from the readily available starting material (2S,4R)-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.

A series of proline-derived α2δ 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.Figure optionsDownload as PowerPoint slide