Novel H3 receptor antagonists with improved pharmacokinetic profiles.
A new series of H(3) antagonists derived from the natural product Conessine are presented. Several compounds from these new series retain the potency and selectivity of earlier diamine based analogs while exhibiting improved PK characteristics. One compound (3u) demonstrated functional antagonism of the H(3) receptor in an in vivo pharmacological model.
Santora
Vincent J
VJ
Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. vsantora@arenapharm.com
Covel
Jonathan A
JA
Hayashi
Rena
R
Hofilena
Brian J
BJ
Ibarra
Jason B
JB
Pulley
Michelle D
MD
Weinhouse
Michael I
MI
Semple
Graeme
G
Ren
Albert
A
Pereira
Guilherme
G
Edwards
Jeffrey E
JE
Suarez
Marissa
M
Frazer
John
J
Thomsen
William
W
Hauser
Erin
E
Lorea
Jodie
J
Grottick
Andrew J
AJ
D000470:Alkaloids / Q000493:pharmacokinetics*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008956:Models, Chemical; D015394:Molecular Structure; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000470:Alkaloids; D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; C007111:conessine