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 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) approximately 300 ng/ml.
Lin
Peter
P
Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065-0900, USA. peter_lin@merck.com
Chang
Lehua
L
Devita
Robert J
RJ
Young
Jonathan R
JR
Eid
Ronsar
R
Tong
Xinchun
X
Zheng
Song
S
Ball
Richard G
RG
Tsou
Nancy N
NN
Chicchi
Gary G
GG
Kurtz
Marc M
MM
Tsao
Kwei-Lan C
KL
Wheeldon
Alan
A
Carlson
Emma J
EJ
Eng
Waisi
W
Burns
H Donald
HD
Hargreaves
Richard J
RJ
Mills
Sander G
SG
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D006801:Humans; D008253:Macaca mulatta; D064729:Neurokinin-1 Receptor Antagonists; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013045:Species Specificity
D064729:Neurokinin-1 Receptor Antagonists; D011759:Pyrrolidines