The proposed research is designed to develop potent inhibitors of the reninangiotensin system as orally active antihypertensive agents. This will be accomplished using two approaches. In the first approach, potent inhibitors of angiotension-converting enzyme (ACE) will be studied. We have already developed inhibitors of this enzyme in which the amide linkage connecting Phe-Gly in the peptide ACE inhibitor Bz-Phe-Gly-Pro has been replaced by a ketomethylene group. Chemical modifications and replacements at the benzamido, phenylalanine, and glycine portions of these potent ACE inhibitors will be performed with the aim of improving ACE inhibition activity in vitro and oral absorption, duration of action, and antihypertensive activity in vivo. The most potent ACE inhibitors will be resynthesized in a radiolabeled form and studied in rats and rabbits for their absorption, distribution, metabolism, and excretion properties. These studies will help guide us in choosing the ACE inhibitors that have the in vivo properties required for a good antihypertensive drug. Studies will also be conducted in hypertensive rats and rabbits to determine the antihypertensive activity of the most potent ACE inhibitors when given orally. In the second approach, the potent renin inhibitor Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys will be modified by a systematic replacement of peptide amide linkages within the molecule with ketomethylene linkages. The purpose of these chemical modifications will be to stabilize this decapeptide to peptidase degradation in vivo and convert it into an orally active renin inhibitor and antihypertensive agent. The new compounds synthesized will be initially tested in vitro as inhibitors of porcine and human renin. Those compounds that retain potent renin inhibition properties in vitro will be tested in vivo in the hypertensive rat and the normotensive and hypertensive monkey. Radiolabeled derivatives of new, potent renin inhibitors will be studied in rats for oral absorption and peptidase resistance properties.