The synthesis of spirapril (5), spiraprilat (25), their RSS stereoisomers, and their glycyl (18b) and lysyl (36, 37) analogues is described. These compounds were evaluated in vivo for inhibition of angiotensin converting enzyme (ACE), and selected compounds were evaluated for in vitro ACE inhibition (spirapril ID50 16 micrograms/kg; spiraprilat IC50 0.8 nM, ID50 8 micrograms/kg). In anesthetized rats, iv, esters 5 and 36 are more potent than enalapril, and diacids 25 and 37 are more potent than enalaprilat in vitro. In the conscious rats, orally, 5 and enalapril (2) showed potent and sustained activity at doses of 0.03-1 and 0.1-1 mg/kg, respectively. From this work, spirapril was selected for clinical evaluation as an antihypertensive agent.