ABSTRACT
A potent series of substituted (2S,4S)-benzylproline α(2)δ ligands have been designed from the readily available starting material (2S,4R)-hydroxy-L-proline. The ligands have improved pharmacokinetic profile over the (4S)-phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development.
Subject(s)
Drug Design , Proline/chemistry , Proline/chemical synthesis , Animals , Humans , Inhibitory Concentration 50 , Ligands , Molecular Structure , Pain , Proline/pharmacology , Rats , SwineABSTRACT
Conformational constraint has been used to design a potent series of α(2)δ 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.
Subject(s)
Drug Design , Hydroxyproline/chemical synthesis , Amines/chemistry , Amines/pharmacokinetics , Animals , Cells, Cultured , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacokinetics , Dogs , Gabapentin , Humans , Hydroxyproline/chemistry , Ligands , Molecular Structure , Protein Subunits/chemistry , Rats , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
A new series of glycine-derived ligands of the α(2)δ subunit of voltage gated calcium channels is described. Several novel compounds (7) based on (6) were prepared that possessed a potency <100 nM in the α(2)δ binding assay.
Subject(s)
Calcium Channels/drug effects , Glycine/chemical synthesis , Ligands , Alkylation , Glycine/chemistry , Glycine/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Protein Subunits/chemistry , Structure-Activity RelationshipABSTRACT
Synthesis of a number of bicyclic five-membered ring derivatives of gabapentin led to the identification of two compounds, (-)-(11A) and (20A) which both had an excellent level of potency against alpha(2)delta and were profiled in an in vivo model of neuropathic pain.