Discovery and in vivo effects of novel human natriuretic peptide receptor A (NPR-A) agonists with improved activity for rat NPR-A

被引：11

作者：

Iwaki, Takehiko ^{[1
]}

Tanaka, Taisaku ^{[1
]}

Miyazaki, Kazuo ^{[1
]}

Suzuki, Yamato ^{[1
]}

Okamura, Yoshihiko ^{[1
]}

Yamaki, Akira ^{[1
]}

Iwanami, Makoto ^{[1
]}

Morozumi, Naomi ^{[1
]}

Furuya, Mayumi ^{[1
]}

Oyama, Yoshiaki ^{[1
]}

机构：

[1] Asubio Pharma Co Ltd, Chuo Ku, 6-4-3 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 24期

关键词：

Natriuretic peptide receptor A; Agonist; Quinazoline derivatives; Pyridopyrimidine derivatives; Congestive heart failure; MECHANISMS;

D O I：

10.1016/j.bmc.2017.11.006

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：

Natriuretic peptide receptor A (NPR-A) agonists were evaluated in vivo by optimizing the structure of quinazoline derivatives to improve agonistic activity for rat NPR-A. A 1,4-Cis-aminocyclohexylurea moiety at 4-position and hydroxy group of D-alaninol at 2-position on the quinazoline ring were found to be important factors in improving rat NPR-A activity. We identified potent quinazoline and pyrido[2,3-d]pyrimidine derivatives against rat NPR-A, with double-digit nanomolar EC50 values. The in vivo results showed that compound 56b administered at 1.0 mg/kg/min significantly increased plasma cGMP concentration and urine volume in rats. We discovered novel potent NPR-A agonists that showed agonistic effects similar to those of atrial natriuretic peptide. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：6680 / 6694

页数：15

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