title: The discovery of potent, selective, and orally bioavailable hNK1 antagonists derived from pyrrolidine.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065-0900, USA. peter_lin@merck.com
authors.forename: Peter
authors.initials: P
authors.lastname: Lin
authors.forename: Lehua
authors.initials: L
authors.lastname: Chang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Devita
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Young
authors.forename: Ronsar
authors.initials: R
authors.lastname: Eid
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Song
authors.initials: S
authors.lastname: Zheng
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Tsou
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: Marc M
authors.initials: MM
authors.lastname: Kurtz
authors.forename: Kwei-Lan C
authors.initials: KL
authors.lastname: Tsao
authors.forename: Alan
authors.initials: A
authors.lastname: Wheeldon
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: Waisi
authors.initials: W
authors.lastname: Eng
authors.forename: H Donald
authors.initials: HD
authors.lastname: Burns
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
mesh_terms: 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
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D011759:Pyrrolidines