4-[6-(2-Aminoethyl)naphthalen-2-yl]benzonitriles are potent histamine H3 receptor antagonists with high CNS penetration.
4-[6-(2-Tertiaryaminoethyl)naphthalen-2-yl]benzonitriles are conformationally constrained histamine H3 receptor antagonists with high potency and selectivity. The analogs were designed around a naphthalene core, with the goal of enhancing lipophilicity and CNS penetration, as compared to a previously reported benzofuran series. The SAR of the tertiary amine moiety is similar to that reported for the benzofuran series, with analogs bearing a 2-methylpyrrolidine substituent possessing the greatest rat and human H3 receptor binding affinities.
Black
Lawrence A
LA
Neuroscience Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA. larry.a.black@abbott.com
Nersesian
Diana L
DL
Sharma
Padam
P
Ku
Yi-Yin
YY
Bennani
Youssef L
YL
Marsh
Kennan C
KC
Miller
Thomas R
TR
Esbenshade
Timothy A
TA
Hancock
Arthur A
AA
Cowart
Marlon
M
D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009281:Naphthalenes; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010539:Permeability; D011485:Protein Binding; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D006633:Histamine Antagonists; D009281:Naphthalenes; D009570:Nitriles; D018100:Receptors, Histamine H3; C031721:naphthalene; C014356:benzonitrile