Design and evaluation of novel biphenyl sulfonamide derivatives with potent histamine H(3) receptor inverse agonist activity.
J Med Chem
; 52(18): 5603-11, 2009 Sep 24.
Article
in En
| MEDLINE
| ID: mdl-19722526
ABSTRACT
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.
Full text:
1
Database:
MEDLINE
Main subject:
Sulfonamides
/
Biphenyl Compounds
/
Drug Design
/
Receptors, Histamine H3
/
Drug Inverse Agonism
/
Histamine Antagonists
Limits:
Animals
/
Humans
/
Male
Language:
En
Year:
2009
Type:
Article