Discovery of new SCH 39166 analogs as potent and selective dopamine D1 receptor antagonists.
A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.
Qiang
Li
L
Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Sasikumar
T K
TK
Burnett
Duane A
DA
Su
Jing
J
Tang
Haiqun
H
Ye
Yuanzan
Y
Mazzola
Robert D
RD
Zhu
Zhaoning
Z
McKittrick
Brian A
BA
Greenlee
William J
WJ
Fawzi
Ahmad
A
Smith
Michelle
M
Zhang
Hongtao
H
Lachowicz
Jean E
JE
D000818:Animals; D001552:Benzazepines / Q000737:chemistry* / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000502:physiology
D001552:Benzazepines; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; C058081:ecopipam