Design, synthesis, and evaluation of novel 2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-b][1,5]oxazocin-5-ones as NK1 antagonists

被引：31

作者：

Seto, S ^{[1
]}

Tanioka, A ^{[1
]}

Ikeda, M ^{[1
]}

Izawa, S ^{[1
]}

机构：

[1] Kyorin Pharmaceut Co Ltd, Discovery Res Labs, Nogi, Tochigi 3290114, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2005年 / 13卷 / 20期

关键词：

NK1; antagonist; pyrimido[4,5-b][1,5]oxazocine; effective bladder capacity; KRP-103;

D O I：

10.1016/j.bmc.2005.06.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of novel bicyclic pyrimidine derivatives was prepared as part of a search for NK1 antagonist aimed at the treatment of urinary incontinence. Among them, 3g, a pyrimido[4,5-b][1,5]oxazocine derivative, bearing a 4-acetylpiperazinyl group and a 2-methylphenyl group, was shown to have potent NK1 antagonist activity with a K-B value of 0.105 nM and markedly increased the effective bladder capacity of guinea pigs (59.4% at 0.3 mg/kg iv and 62.8% at 3 mg/kg id). Furthermore, the effect of 3g on bladder function appeared to differ from that of tolterodine, another classical anti-pollakiuria agent, as determined by the distention-induced rhythmic bladder contraction assay using a urethane-anesthetized guinea pig model. Compound 3g is expected to be a promising agent for the treatment of urinary incontinence. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：5717 / 5732

页数：16