Issei Tsukamoto

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.

Recent patenting activities in the discovery and development of vasopressin V2 receptor agonists.

Introduction: Vasopressin V2 agonists are well known as effective therapies in the treatment of central diabetes insipidus and nocturnal enuresis. Furthermore, given their mode of action, these particular agonists have more recently been considered, in both the pharmaceutical industry and in academia, as viable therapies for urological conditions such as nocturia. Areas covered: For the past 10 years, significant progress has been made in the discovery and development of vasopressin V2 agonists. This article provides the reader with information on the recent progress in the discovery and development of these compounds based on patents published from 2002 onward. Specifically, the article looks at the discovery of new non-peptide agonists as well as well as novel formulations of the vasopressin V2 agonist desmopressin. Expert opinion: The V2 receptor is currently one of the hottest therapeutic targets investigated for the treatment of urinary disorders such as nocturia and central diabetes. Over the past 10 years, significant progress has been made in the discovery and development of vasopressin V2 receptor agonists, for the treatment of these disorders. The author anticipates that these agonists will be launched to market in the not-too-distant future.

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.