A series of renin inhibitors having alpha-heteroatom amino acids as P2 substitutions has been prepared. Examples where the heteroatom is oxygen, sulfur, or nitrogen are described. Many of the compounds exhibit subnanomolar potency when tested in vitro against monkey renin. When selected compounds were tested orally in conscious, salt-depleted, normotensive, Cynomolgus monkeys, low to moderate blood pressure lowering was observed. At an oral dose of 30 mg/kg, compound 53a lowered blood pressure by a maximum of 18 mmHg at 2.5 h post-dose.