Design and evaluation of novel biphenyl sulfonamide derivatives with potent histamine H(3) receptor inverse agonist activity.
Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.
Covel
Jonathan A
JA
Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. jcovel@arenapharm.com
Santora
Vincent J
VJ
Smith
Jeffrey M
JM
Hayashi
Rena
R
Gallardo
Charlemagne
C
Weinhouse
Michael I
MI
Ibarra
Jason B
JB
Schultz
Jeffrey A
JA
Park
Douglas M
DM
Estrada
Scott A
SA
Hofilena
Brian J
BJ
Pulley
Michelle D
MD
Smith
Brian M
BM
Ren
Albert
A
Suarez
Marissa
M
Frazer
John
J
Edwards
Jeffrey
J
Hauser
Erin K
EK
Lorea
Jodie
J
Semple
Graeme
G
Grottick
Andrew J
AJ
D000284:Administration, Oral; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry*; D015195:Drug Design; D054314:Drug Inverse Agonism; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013894:Thirst / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects
D001713:Biphenyl Compounds; D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; D013449:Sulfonamides; C010574:biphenyl