4-phenoxypiperidines: potent, conformationally restricted, non-imidazole histamine H3 antagonists.
Two new series of 4-(1-alkyl-piperidin-4-yloxy)-benzonitriles and 4-(1-isopropyl-piperidin-4-yloxy)-benzylamines have been prepared. In vitro activity was determined at the recombinant human H(3) receptor and several members of these new series were found to be potent H(3) antagonists. The present compounds contain a 4-phenoxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole histamine H(3) ligands. One selected member of the new series, 4-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-morpholine (13g), was found to be a potent, highly selective H(3) receptor antagonist with in vivo efficacy in a rat EEG model of wakefulness at doses as low as 1 mg/kg sc.
Dvorak
Curt A
CA
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA. cdvorak@prdus.jnj.com
Apodaca
Richard
R
Barbier
Ann J
AJ
Berridge
Craig W
CW
Wilson
Sandy J
SJ
Boggs
Jamin D
JD
Xiao
Wei
W
Lovenberg
Timothy W
TW
Carruthers
Nicholas I
NI
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004569:Electroencephalography; D004576:Electromyography; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship; D014851:Wakefulness / Q000187:drug effects
D006633:Histamine Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3