Diamine-based human histamine H3 receptor antagonists: (4-aminobutyn-1-yl)benzylamines.
A series of (4-aminobutyn-1-yl)benzylamines were prepared and the SAR around three key areas: (1) the amine attached to the butynyl linker (R(3)R(4)N-); (2) the benzylamine moiety (R(1)R(2)N-); and (3) the point of attachment of the benzylamine group (R(1)R(2)N- in the ortho, meta, or para positions) was examined. One compound, 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine (9s) was chosen for further profiling and found to be a selective histamine H(3) antagonist with desirable drug-like properties. Ex vivo receptor occupancy studies established that 9s does occupy H(3) binding sites in the brain of rats after oral administration. Subcutaneous doses of 9s (10mg/kg) given during the natural sleep phase demonstrated robust wake-promoting effects.
Dvorak
Curt A
CA
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, CA 92121, USA. cdvorak@its.jnj.com
Apodaca
Richard
R
Xiao
Wei
W
Jablonowski
Jill A
JA
Bonaventure
Pascal
P
Dugovic
Christine
C
Shelton
Jonathan
J
Lord
Brian
B
Miller
Kirsten
K
Dvorak
Lisa K
LK
Lovenberg
Timothy W
TW
Carruthers
Nicholas I
NI
D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D003959:Diamines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014851:Wakefulness / Q000187:drug effects
D001596:Benzylamines; D003959:Diamines; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3