Ceronapril is a phosphonate angiotensin-converting enzyme inhibitor that was being developed by Bristol-Myers Squibb for the treatment of hypertension. In spontaneously hypertensive rats, Ceronapril narrowed the autoregulatory range and shifted it to lower pressures. In in vitro experiments, Ceronapril inhibited ACE in slices of the brain with an IC50 of approximately 34 nM, as measured by in vitro autoradiography. In C.S.F. ACE was inhibited with an IC50 of approximately 34 nM, as assessed by a fluorimetric enzyme assay. Ceronapril (100 mg/kg, p.o.) inhibited ACE in plasma, kidney, and lung rapidly (3 hr) after administration. Inhibition of ACE in kidney lasted up to 48 hr after administration of Ceronapril, whereas the activity of ACE in plasma and lung recovered rapidly (8 hr). In lung and plasma ACE was increased at 72 hr after administration. Therefore, induction of ACE in plasma and lung by the drug may partly obscure the acute inhibition and may contribute to the different time-course of inhibition of ACE from the kidney. Ceronapril inhibited ACE in the vascular organ of the lamina terminals (OVLT) and subfornical organ (SFO) of the brain slowly (onset at 8 hr) but persistently (from 24 to 48 hr). However, the drug did not inhibit ACE in structures of the brain within the blood-brain barrier, such as the caudate-putamen, choroid plexus, globus pallidus, supraoptic nucleus and paraventricular nucleus of the hypothalamus.