Chikashi Saitoh

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.

Preparation of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide derivatives as novel arginine vasopressin V2 receptor agonists

The present work describes the discovery of novel series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives as arginine vasopressin (AVP) V(2) receptor agonists. By replacing the amide juncture in YM-35278 with a direct ring connection gave compound 10a, which acts as a V(2) receptor agonist. These studies provided the potent, orally active non-peptidic V(2) receptor agonists 10a and 10j.

Optimization of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives as arginine vasopressin V2 receptor agonists and discussion of their binding modes.

A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives were optimized to achieve potent agonistic activity, both in vitro and in vivo, for the arginine vasopressin V(2) receptor, resulting in the eventual discovery of compound 1g. Molecular modeling of compound 1g with V(2) receptor was also examined to evaluate the binding mode of this series of compounds.

Functional Role of β3-Adrenoreceptors in the Bladder

The detrusor muscle contains β‐adrenoceptors (β‐AR) and three subtypes, such as β1‐AR, β2‐AR, and β3‐AR, which have been identified in most species. There is a predominant expression of β3‐AR messenger RNA in human bladder tissue when compared with the β1‐AR and β2‐AR subtypes. Moreover, the presence of β1, β2, and β3‐AR in the human urothelium has been identified. It has also been demonstrated in animals that relaxation mediated through βs‐AR is achieved solely by cAMP‐dependent mechanisms in non‐contracted detrusor muscles, whereas in KCl precontracted detrusor muscles, cAMP‐dependent and ‐independent mechanisms by way of calcium‐activated K +(BK Ca) channels may be involved in β‐adrenergic relaxation. In addition, a recent phase II proof‐of‐concept study using a novel selective β3‐adrenoceptor agonist (YM178) has shown clinical efficacy in the treatment of overactive bladder (OAB) symptoms, suggesting that β3‐AR should be used as a therapeutic target for the treatment of OAB disorders.