Discovery and in vivo effects of novel human natriuretic peptide receptor A (NPR-A) agonists with improved activity for rat NPR-A. Issue 24 (15th December 2017)

• Record Type: Journal Article
• Authors: Iwaki, Takehiko; Tanaka, Taisaku; Miyazaki, Kazuo; Suzuki, Yamato; Okamura, Yoshihiko; Yamaki, Akira; Iwanami, Makoto; Morozumi, Naomi; Furuya, Mayumi; Oyama, Yoshiaki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 24(2017)
• Page Start: 6680
• Page End: 6694
• Publication Date: 2017-12-15
• Subjects: Natriuretic peptide receptor A -- Agonist -- Quinazoline derivatives -- Pyridopyrimidine derivatives -- Congestive heart failure; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.11.006
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 ofd -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 compound56b 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.