Heterocyclic replacement of the central phenyl core of diamine-based histamine H3 receptor antagonists.
A series of small molecules consisting of a heterocyclic core flanked by two basic functionalities were synthesized and screened for in vitro affinity at the human histamine H(3) receptor (hH(3)R). Nine of the twenty-eight compounds tested were found to possess a hH(3)R K(i) of less than 5 nM and consisted of a diverse range of central hetero-aromatic linkers (pyridine, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, and pyrrole). One member of this series, (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone (37), was found to be a high affinity, selective antagonist that crosses the blood-brain barrier and occupies H(3) receptors after oral administration in the rat.
Swanson
Devin M
DM
Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121, United States. dswanso1@its.jnj.com
Shah
Chandra R
CR
Lord
Brian
B
Morton
Kirsten
K
Dvorak
Lisa K
LK
Mazur
Curt
C
Apodaca
Richard
R
Xiao
Wei
W
Boggs
Jamin D
JD
Feinstein
Mark
M
Wilson
Sandy J
SJ
Barbier
Ann J
AJ
Bonaventure
Pascal
P
Lovenberg
Timothy W
TW
Carruthers
Nicholas I
NI
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002460:Cell Line; D003959:Diamines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054828:Histamine H3 Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*
D003959:Diamines; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3