Cyclopentane-based human NK1 antagonists. Part 2: development of potent, orally active, water-soluble derivatives.
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.
Meurer
Laura C
LC
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. laura_meurer@merck.com
Finke
Paul E
PE
Owens
Karen A
KA
Tsou
Nancy N
NN
Ball
Richard G
RG
Mills
Sander G
SG
Maccoss
Malcolm
M
Sadowski
Sharon
S
Cascieri
Margaret A
MA
Tsao
Kwei-Lan
KL
Chicchi
Gary G
GG
Egger
Linda A
LA
Luell
Silvi
S
Metzger
Joseph M
JM
Macintyre
D Euan
DE
Rupniak
Nadia M J
NM
Williams
Angela R
AR
Hargreaves
Richard J
RJ
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
D003517:Cyclopentanes; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D014867:Water