Orally Active Aminopeptidase A Inhibitor Prodrugs: Current State and Future Directions

Curr Hypertens Rep. 2019 May 21;21(7):50. doi: 10.1007/s11906-019-0957-4.


Purpose of review: To review the data supporting the use of aminopeptidase A (APA) inhibitor prodrugs as centrally acting antihypertensive agents.

Recent findings: Brain renin-angiotensin system (RAS) hyperactivity has been implicated in the development and maintenance of hypertension. Angiotensin III, generated by APA, one of the main effector peptides of the brain RAS, exerts a tonic stimulatory control over blood pressure in hypertensive rats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, leading to the development of RB150/firibastat, an orally active prodrug of the specific and selective APA inhibitor, EC33. When given orally, RB150/firibastat crosses the gastrointestinal and blood-brain barriers, enters the brain, and generates two active molecules of EC33 which inhibit brain APA activity, blocking brain angiotensin III formation, and decrease blood pressure for several hours in hypertensive rats. Orally active APA inhibitor prodrugs, by blocking brain RAS activity, represent promising novel strategy for treating hypertension.

Keywords: Aminopeptidase A inhibitor; Brain renin–angiotensin system; Hypertension.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Angiotensin II
  • Animals
  • Antihypertensive Agents
  • Blood Pressure
  • Brain / physiology
  • Glutamyl Aminopeptidase* / administration & dosage
  • Humans
  • Hypertension* / drug therapy
  • Prodrugs* / administration & dosage
  • Rats
  • Renin-Angiotensin System / physiology*


  • Antihypertensive Agents
  • Prodrugs
  • Angiotensin II
  • Glutamyl Aminopeptidase