title: Cyclopentane-based human NK1 antagonists. Part 1: discovery and initial SAR.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. paul_finke@merck.com
authors.forename: Paul E
authors.initials: PE
authors.lastname: Finke
authors.forename: Laura C
authors.initials: LC
authors.lastname: Meurer
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Levorse
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Malcolm
authors.initials: M
authors.lastname: Maccoss
authors.forename: Sharon
authors.initials: S
authors.lastname: Sadowski
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: Kwei-Lan
authors.initials: KL
authors.lastname: Tsao
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.forename: D Euan
authors.initials: DE
authors.lastname: Macintyre
mesh_terms: 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
chemical_list: D003517:Cyclopentanes; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1