Discovery and in vivo effects of novel human Natriuretic Peptide Receptor A (NPR-A) agonists with improved activity for rat NPR-A

Publication date: Available online 6 November 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Takehiko Iwaki, Taisaku Tanaka, Kazuo Miyazaki, Yamato Suzuki, Yoshihiko Okamura, Akira Yamaki, Makoto Iwanami, Naomi Morizumi, Mayumi Furuya, Yoshiaki Oyama
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.

Graphical abstract

http://ift.tt/2iAg2A0