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

Bioorg Med Chem. 2017 Dec 15;25(24):6680-6694. doi: 10.1016/j.bmc.2017.11.006. Epub 2017 Nov 6.

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 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.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Male
  • Molecular Structure
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Atrial Natriuretic Factor / agonists*
  • Structure-Activity Relationship

Substances

  • Quinazolines
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor A