Benzimidazole- and indole-substituted 1,3'-bipyrrolidine benzamides as histamine H3 receptor antagonists.
Using a focused screen of biogenic amine compounds we identified a novel series of H(3)R antagonists. A preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimization of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and efficacy in both water intake and novel object recognition models.
Cole
Derek C
DC
Chemical Sciences, Wyeth Research, 401 N Middletown Rd. Pearl River, NY 10965, United States. coledc@wyeth.com
Gross
Jonathan L
JL
Comery
Thomas A
TA
Aschmies
Suzan
S
Hirst
Warren D
WD
Kelley
Cody
C
Kim
Ji-In
JI
Kubek
Katie
K
Ning
Xiaoping
X
Platt
Brian J
BJ
Robichaud
Albert J
AJ
Solvibile
William R
WR
Stock
Joseph R
JR
Tawa
Gregory
G
Williams
Marla J
MJ
Ellingboe
John W
JW
D000818:Animals; D001549:Benzamides / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D001562:Benzimidazoles / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D018938:Caco-2 Cells; D002460:Cell Line; D054828:Histamine H3 Antagonists / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011759:Pyrrolidines / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D018100:Receptors, Histamine H3 / Q000097:blood / Q000378:metabolism
D001549:Benzamides; D001562:Benzimidazoles; D054828:Histamine H3 Antagonists; D007211:Indoles; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C031000:benzimidazole