Nonpeptide arginine vasopressin antagonists for both V(1A) and V2 receptors: Synthesis and pharmacological properties of 4'-(1,4,5,6- tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)benzanilide derivatives and 4'-(5,6-dihydro-4H-thiazolo[5,4-d] [1]benzoazepine-6-carbonyl)benzanilide derivatives

DOI: 10.1248/cpb.48.21

Source and publish data:

Chemical and Pharmaceutical Bulletin p. 21 - 31 (2000)

Update date:2022-08-02

Topics:

Authors:

Matsuhisa, Akira

Taniguchi, Nobuaki

Koshio, Hiroyuki

Yatsu, Takeyuki

Tanaka, Akihiro

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Article abstract of DOI:10.1248/cpb.48.21

Arginine vasopressin (AVP) has a dual action mainly in the periphery, i.e., vasoconstriction and water reabsorption via V(1A) and V₂ receptors; it may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of orally active AVP antagonists for both V(1A) and V₂ receptors based on the hypothesis that the blockade of both V(1A) and V₂ receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-(1,4,5,6- tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)benzanilide and 4'-(5,6- dihydro-4H-thiazolo[5,4-d][1]benzoazepine-6-carbonyl)benzanilide were synthesized and examined for AVP antagonist activity for both V(1A) and V₂ receptors. As a result, it was found that the 4'-(1,4,5,6- tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide derivatives showed potent binding affinity for both V(1A) and V₂ receptors. Especially, 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6- carbonyl)-2-phenylbenzanilide monohydrochloride (18, YM087=conivaptan hydrochloride) exhibited potent binding affinity and AVP antagonist activity, after intravenous administration, for both V(1A) and V₂ receptors. Furthermore, YM087 exhibited the most potent oral activity for the V₂ receptor. Details of the synthesis and pharmacological properties of this series are presented.