Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine h(4) antagonists.
Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
Venable
Jennifer D
JD
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA. jvenable@prdus.jnj.com
Cai
Hui
H
Chai
Wenying
W
Dvorak
Curt A
CA
Grice
Cheryl A
CA
Jablonowski
Jill A
JA
Shah
Chandra R
CR
Kwok
Annette K
AK
Ly
Kiev S
KS
Pio
Barbara
B
Wei
Jianmei
J
Desai
Pragnya J
PJ
Jiang
Wen
W
Nguyen
Steven
S
Ling
Ping
P
Wilson
Sandy J
SJ
Dunford
Paul J
PJ
Thurmond
Robin L
RL
Lovenberg
Timothy W
TW
Karlsson
Lars
L
Carruthers
Nicholas I
NI
Edwards
James P
JP
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4
D001562:Benzimidazoles; C418607:HRH4 protein, human; D006633:Histamine Antagonists; D007211:Indoles; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4