YL-(S)-3-(2-NAPHTHYL)ALANYL-N-BENZYL-N-METHYLAMIDE (SDZ-NKT-343), A POTENT HUMAN NK1 TACHYKININ RECEPTOR ANTAGONIST WITH GOOD ORAL ANALGESIC ACTIVITY IN CHRONIC PAIN MODELS

A lead compound which had sub-micromolar affinity for the rabbit NK1 r eceptor but negligible affinity for rat NK1 receptors, 3a, was discove red by directed screening. 2-Substitution in the ring of the benzylthi ourea substituent in the initial lead was found to be important, and h alogens (Cl, Br) in this position were found to improve affinity for t he human receptor. The activity of a series of 2-halo-substituted benz ylthioureas was then optimized by modification of the proline diphenyl methyl amide, guided by a simple conceptual model based on structural overlay between these early antagonists and NK1 selective peptides. In this way, aromatic amino acid amides were identified which had improv ed affinity with respect to the starting diphenylmethyl (DPM) amides. The first sub-nanomolar ligand for the human NK1 receptor which arose from this series, 4af, combined a 2-chlorobenzylthiourea unit with a 2 -naphthylalanine amide. Contemporaneously it was discovered that the b enzylthiourea unit could be simplified to a phenylthiourea providing t hat an appropriate 2-substituent was also incorporated. Combination of these two series gave 2-NO2 phenylthiourea analogues which led direct ly to the analogous urea, l-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methyl amide, SDZ NKT 343), a highly potent ligand for the human NK1 receptor (K-i = 0.16 nM). In addition to its high in vitro potency, 5f proved to be a potent orally active analgesic in guinea pig models of chronic inflammatory and neuropathic pain. The nature of the 2-aryl substitue nt was found to be critical for oral activity in this series. Clinical evaluation of 5f as a novel analgesic agent is currently underway.