Fused bicyclic pyrrolizinones as new scaffolds for human NK1 antagonists.
Previous work on human NK(1) antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single active diastereomer, is described.
Morriello
Gregori J
GJ
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Devita
Robert J
RJ
Mills
Sander G
SG
Young
Jonathan R
JR
Lin
Peter
P
Doss
George
G
Chicchi
Gary G
GG
Demartino
Julie
J
Kurtz
Marc M
MM
Tsao
Kwei-Lan C
KL
Carlson
Emma
E
Townson
Karen
K
Wheeldon
Alan
A
Boyce
Susan
S
Collinson
Neil
N
Rupniak
Nadia
N
Moore
Stephen
S
D000577:Amides / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000737:chemistry; D006801:Humans; D006900:Hydroxylation; D008745:Methylation; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013237:Stereoisomerism; D014508:Urea / Q000737:chemistry
D000577:Amides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004852:Epoxy Compounds; D064729:Neurokinin-1 Receptor Antagonists; D011758:Pyrroles; D018040:Receptors, Neurokinin-1; D014508:Urea