2-Aryl indole NK1 receptor antagonists: optimisation of the 2-aryl ring and the indole nitrogen substituent.
Novel 2-aryl indole hNK1 receptor ligands were prepared utilising palladium cross-coupling chemistry of a late intermediate as a key step. Compounds with high hNK1 receptor binding affinity and good brain penetration (e.g., 9d) were synthesised.
Dinnell
K
K
Department of Medicinal Chemistry, Merck, Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, Essex, UK. kevin_dinnell@merck.com
Chicchi
G G
GG
Dhar
M J
MJ
Elliott
J M
JM
Hollingworth
G J
GJ
Kurtz
M M
MM
Ridgill
M P
MP
Rycroft
W
W
Tsao
K L
KL
Williams
A R
AR
Swain
C J
CJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D004583:Electrons; D005849:Gerbillinae; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008968:Molecular Conformation; D064729:Neurokinin-1 Receptor Antagonists; D009584:Nitrogen / Q000737:chemistry; D011994:Recombinant Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship; D013373:Substance P / Q000378:metabolism
D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D011994:Recombinant Proteins; D013373:Substance P; D009584:Nitrogen