Novel design of nonpeptide AVP V(2) receptor agonists: structural requirements for an agonist having 1-(4-aminobenzoyl)-2,3,4, 5-tetrahydro-1H-1-benzazepine as a template.
The discovery of a series of nonpeptide arginine vasopressin V(2) receptor agonists is described. After identifying the aniline derivative 8 as our lead compound from the metabolites of compound 7 that showed antidiuretic activity by po administration to Brattleboro rats, improvements in the in vitro potency involving evaluations of the structural requirements for agonist action and optimizing the structure of the benzoyl moiety have been intensively undertaken. These studies led to compounds 16g, 19a, and 23b,h,i that show potent agonist activity for the V(2) receptor.
Kondo
K
K
Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Company, 463-10 Kagasuno Kawauchi-cho, Tokushima 771-0192, Japan. k_kondo@research.otsuka.co.jp
Ogawa
H
H
Shinohara
T
T
Kurimura
M
M
Tanada
Y
Y
Kan
K
K
Yamashita
H
H
Nakamura
S
S
Hirano
T
T
Yamamura
Y
Y
Mori
T
T
Tominaga
M
M
Itai
A
A
D000284:Administration, Oral; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism*; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004231:Diuresis / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D017483:Receptors, Vasopressin / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001552:Benzazepines; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D000242:Cyclic AMP