The discovery of potent, selective, and orally bioavailable hNK 1 antagonists derived from pyrrolidine

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 18; pp. 5191 - 5198
• Main Authors: Lin, Peter, Chang, Lehua, DeVita, Robert J., Young, Jonathan R., Eid, Ronsar, Tong, Xinchun, Zheng, Song, Ball, Richard G., Tsou, Nancy N., Chicchi, Gary G., Kurtz, Marc M., Tsao, Kwei-Lan C., Wheeldon, Alan, Carlson, Emma J., Eng, WaiSi, Burns, H. Donald, Hargreaves, Richard J., Mills, Sander G.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 2007
• Subjects: Neurokinin NK 1 antagonist; NK 1; Substance P antagonist; Tachykinin NK 1 antagonist; Substance P antagonist; Neurokinin NK 1 antagonist; Tachykinin NK 1 antagonist; NK 1
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.06.085

SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK 1 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 Occ 90 ∼ 300 ng/ml. SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK 1 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 Occ 90 ∼ 300 ng/ml.