Seven ACE inhibitors were studied for possible differences in distribution to aorta, brain, heart, lung, and kidney after administration of single oral doses to spontaneously hypertensive rats (SHR). Doses, normalized for differences in inhibitory potency and molecular weight, were expected to deliver equivalent levels of ACE-inhibitory activity to the circulation, and this was confirmed by preliminary dose-response studies. The relative potencies of the active moieties of the seven drugs and the normalized oral doses used were: SQ 29,852 (1.0), 100 mg/kg; captopril (3.5), 30 mg/kg; enalapril (12), 20 mg/kg; fosinopril (13), 25 mg/kg; zofenopril (20), 10 mg/kg; lisinopril (24), 10 mg/kg; and ramipril (51), 5 mg/kg. In these ex vivo studies, ACE activities were determined fluorometrically in SHR sera and in uncentrifuged homogenates of the solid tissues at various times after oral dosing with the ACE inhibitors. As expected, the normalized oral doses of the seven inhibitors had equivalent effects on serum ACE. In lung, where ACE has a vascular endothelial localization, and in aorta, where ACE inhibition correlates with antihypertensive action, ramipril, lisinopril, and zofenopril were distinguished by the magnitude and duration (three to four days) of their effects. In the brain, where ACE may affect central regulation of blood pressure and participate in the degradation of certain neuropeptides, ramipril and enalapril had no effect; captopril and zofenopril had modest, short-lasting effects, and fosinopril, lisinopril, and SQ 29,852 had delayed but long-lasting inhibitory actions. In the kidney, where ACE inhibition may have positive or negative effects on renal function, ramipril and fosinopril could be distinguished by their weak actions, perhaps associated with biliary routes of excretion. In the heart, where ACE inhibitors may prevent ischemic damage to the myocardium, single oral doses of captopril, fosinopril, and particularly zofenopril produced striking and long-lasting inhibition, whereas equivalent doses of ramipril and enalapril produced barely detectable inhibition.

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The synthesis of a series of orally active, phosphinyloxyacyl proline inhibitors of angiotensin converting enzyme (ACE) is described. The in vitro and in vivo ACE inhibitory activities are reported for each compound. The structure-activity relationship for this series of compounds in relation to the carboxyalkyl dipeptide ACE inhibitors as well as other types of hydroxyphosphinyl-containing ACE inhibitors (e.g., the corresponding nitrogen and carbon isosteres) is discussed. Within an isosteric series of phosphorus-containing inhibitors based on the lysylproline terminal dipeptide sequence, only the phosphonates (oxygen isosteres) show a high level of oral activity. Optimum potency and oral activity in the phosphonate series occurs with the (phenylbutyl)- and n-hexylphosphonate side chains. An aminobutyl side chain in the P1' residue is an absolute requirement for full expression of oral activity. The most potent of these compounds, 8b (SQ 29,852), has intravenous and oral activities superior in potency to those of captopril in the normotensive rat.

Aortic histamine-forming capacity (HFC) has been examined in relationship to the applied mean shear stress intensity created by pulsatile perfusion of rabbit aortas with platelet-free blood for a 1-h period. Mean shear stress intensities ranged from 22 to 109 dyn/cm2. Results indicate that a high correlation exists between the shear stress and the HFC which is described by the regression equation y = 0.28 x -6.1, where y = HFC and x = mean shear stress intensity. Results suggest that the rate of histamine formation is sensitive to the applied shear stress, and that the histidine decarboxylase system of the aorta may have the potential of serving as one coupling agent between applied hemodynamic stress and resultant alterations in aortic wall resistance to macromolecules.

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