Structure-activity relationships and spectroscopic insights into a series of retro-inverso Tachykinin NK-1 receptor antagonists

The introduction of some selected isosteric modifications to the C-terminal amide group in our cycloalkyl amino acid-based tachykinin NK-1 receptor antagonists resulted in the design and synthesis of MEN 10914 [1] bearing an N-methyl retro-amide group (Fig. 1), which had higher in vitro activity compared to the parent peptide MEN 10725 [2]. However, when MEN 10914 was tested in an in vivo animal model of neurogenic inflammation (plasma protein extravasation in guinea-pig bronchi after agonist challenge), the results were not in accordance with the expected antagonist activity. Nevertheless, the antagonist activity in vitro was interesting enough to select MEN 10914 as a suitable lead candidate for further chemical modifications. The rationale for planning these changes was derived from the hypothesis of the bioactive structure postulated for our series of cyclohexane-based antagonists [2].