Synthesis and structure-activity relationships of amide derivatives of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetic acid as selective arginine vasopressin V2 receptor agonists.
A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide derivatives was synthesized, and their structure-activity relationships were examined in order to identify potent and selective arginine vasopressin V(2) receptor agonists. Attempts to substitute other chemical groups in place of the 2-pyridilmethyl moiety of 1a led to the discovery that potent V(2) binding affinity could be obtained with a wide range of functional groups. This structural tolerance allowed for the manipulation of other attributes, such as selectivity against V(1a) receptor affinity or avoidance of the undesirable inhibition of cytochrome P450 (CYP), without losing potent affinity for the V(2) receptor. Some representative compounds obtained in this study were also found to decrease urine volume in awake rats.
Tsukamoto
Issei
I
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
Koshio
Hiroyuki
H
Kuramochi
Takahiro
T
Saitoh
Chikashi
C
Yanai-Inamura
Hiroko
H
Kitada-Nozawa
Chika
C
Yamamoto
Eisaku
E
Yatsu
Takeyuki
T
Shimada
Yoshiaki
Y
Sakamoto
Shuichi
S
Tsukamoto
Shin-ichi
S