title: Cyclopentane-based human NK1 antagonists. Part 2: development of potent, orally active, water-soluble derivatives.
abstract: The synthesis and optimization of a cyclopentane-based hNK1 antagonist scaffold 3, having four chiral centers, will be discussed in the context of its enhanced water solubility properties relative to the marketed anti-emetic hNK1 antagonist EMEND (Aprepitant). Sub-nanomolar hNK1 binding was achieved and oral activity comparable to Aprepitant in two in vivo models will be described.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. laura_meurer@merck.com
authors.forename: Laura C
authors.initials: LC
authors.lastname: Meurer
authors.forename: Paul E
authors.initials: PE
authors.lastname: Finke
authors.forename: Karen A
authors.initials: KA
authors.lastname: Owens
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Tsou
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
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: Linda A
authors.initials: LA
authors.lastname: Egger
authors.forename: Silvi
authors.initials: S
authors.lastname: Luell
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.forename: D Euan
authors.initials: DE
authors.lastname: Macintyre
authors.forename: Nadia M J
authors.initials: NM
authors.lastname: Rupniak
authors.forename: Angela R
authors.initials: AR
authors.lastname: Williams
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hargreaves
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003517:Cyclopentanes / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: D003517:Cyclopentanes; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D014867:Water