Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists.
A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9μMh.
Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Qingbei
Q
Zeng
Stuart B
SB
Rosenblum
Zhaoxia
Z
Yang
Yueheng
Y
Jiang
Kevin D
KD
McCormick
Robert G
RG
Aslanian
Luli
L
Duguma
Joseph A
JA
Kozlowski
Neng-Yang
NY
Shih
John A
JA
Hey
Robert E
RE
West
Walter A
WA
Korfmacher
Michael
M
Berlin
Christopher W
CW
Boyce
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006168:Guinea Pigs; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3; C014353:benzimidazolone; D003577:Cytochrome P-450 Enzyme System
Benzimidazolone; H(3)-antagonists; P450 inhibition