D-amino acid homopiperazine amides: discovery of A-320436, a potent and selective non-imidazole histamine H(3)-receptor antagonist.
Structure-activity relationships of homopiperazine-containing alkoxybiaryl nitriles employing various D-amino acid moieties and their N-furanoyl analogues were undertaken. This led to A-320436, a potent and selective non-imidazole H(3)-receptor antagonist possessing balanced affinity for both rat and human H(3)-receptors. This compound was shown to demonstrate in vitro and in vivo functional antagonism and is non-neurotoxic at doses (i.p.) up to 163 mg/kg in a general observation test.
Curtis
Michael P
MP
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. michael.curtis@abbott.com
Dwight
Wesley
W
Pratt
John
J
Cowart
Marlon
M
Esbenshade
Timothy A
TA
Krueger
Kathy M
KM
Fox
Gerard B
GB
Pan
Jia Bao
JB
Pagano
Thomas G
TG
Hancock
Arthur A
AA
Faghih
Ramin
R
Bennani
Youssef L
YL
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D006633:Histamine Antagonists; D010879:Piperazines; D018100:Receptors, Histamine H3