Cyclopentane-based human NK1 antagonists. Part 1: discovery and initial SAR.
An initial investigation of the novel cyclopentane scaffold 6 afforded low nanomolar human NK1 antagonists having enhanced water solubility properties compared to morpholine 1. A synthesis of this cyclopentane scaffold, having three contiguous chiral centers, and the unexpected determination that the 1,2-trans-2,3-trans-ring stereochemistry, as opposed to the cis-ether/phenyl configuration of the known structures 1-5, is optimal for this class of antagonist are described.
Finke
Paul E
PE
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. paul_finke@merck.com
Meurer
Laura C
LC
Levorse
Dorothy A
DA
Mills
Sander G
SG
Maccoss
Malcolm
M
Sadowski
Sharon
S
Cascieri
Margaret A
MA
Tsao
Kwei-Lan
KL
Chicchi
Gary G
GG
Metzger
Joseph M
JM
Macintyre
D Euan
DE
D003517:Cyclopentanes / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
D003517:Cyclopentanes; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1