Analogs of captopril and enalapril with a thiorphan-like substituent at the 4-position of the proline ring were synthesized and found to be dual inhibitors of angiotensin converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). Angiotensin converting enzyme (ACE) inhibitors are one of the most widely used classes of antihypertensive agents today. Captopril and enalapril, the two most prescribed ACE inhibitors, are effective in treating nearly half of all the hypertensive patients. When coadministered with a diuretic, their efficacy level goes up significantly. Diuretics have many undesired side effects such as aldosterone secretion, elevation of plasma renin levels, and nonspecific ion excretion leading to hypokalemia. Inhibitors of neutral endopeptidase (NEP), on the other hand, have been found to produce diuresis with selective natriuresis in animal models and in humans. It has been hypothesized that the combined action of inhibitors of ACE and NEP would produce a potent antihypertensive effect with fewer side effects than by a combination of an ACE inhibitor and a diuretic. Therefore, we decided to synthesize and evaluate compounds that inhibit both ACE and NEP. ACE and NEP are zinc metalloenzymes that are inhibited by captopril and thiorphan respectively. We decided to design a novel series of compounds by joining these two structures with a variety of linkers. The structure activity relationship (SAR) for each compound was therefore examined. It has been found that placing a substituent at the 4-position of the proline ring of captopril and enalapril, as exemplified by zofenopril and spirapril, leads to potent and long acting ACE inhibitors. We decided to link a thiorphan-like structure at this position. It has been reported that the carboxylic acid of thiorphan could be extended out, as exemplified by SQ 29072, with little loss in activity. Keeping these considerations in mind, we designed the following initial targets in which the zinc chelating group, the P1' residue and the amide linkage necessary for the NEP inhibitory activity are attached to the 4-position of the proline ring of captopril and enalapril. The carboxylic acid group in these targets serves as the C-terminal acid required for both ACE and NEP inhibitory activities.