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.
Keywords: Agonist; Congestive heart failure; Natriuretic peptide receptor A; Pyridopyrimidine derivatives; Quinazoline derivatives.
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