α,α-Cyclic aminoacids as useful scaffolds for the preparation of hNK2 receptor antagonists

MEN 15596 is a small molecule, potent and selective antagonist of NK2 receptor, possessing high affinity and potency at the guinea-pig and human receptors whose pharmacological characterization has been recently published. Here we report how the corresponding class of compounds was derived from a tri-peptide library and the first optimization round to improve both in vitro activity and physicochemical properties.

Graphical abstractIn the search for a novel class of hNK2 antagonists, compound 1 was identified from a tripeptide library. Subsequent optimization of binding affinity and physicochemical properties afforded 43, subnanomolar hNK2 antagonist.Figure optionsDownload full-size imageDownload as PowerPoint slide