The discovery of potent, selective, and orally bioavailable hNK1 antagonists derived from pyrrolidine

SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK1 antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ90 ∼ 300 ng/ml.

Graphical abstractSAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK1 antagonists. One vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ90 ∼ 300 ng/ml.Figure optionsDownload full-size imageDownload as PowerPoint slide