Renin Inhibitors

Definition
Renin inhibitors represent an alternative to angiotensin-converting enzyme inhibitors (ACEI) for the treatment of hypertension. They inhibit the renin-angiotensin system at its first and rate limiting step, the renin-angiotensinogen reaction 1.

Related Peptides
Renin can be inhibited by peptides derived from its prosegment. The design of compounds based on pepstatin and on angiotensinogen sequence has led to very potent and specific human renin inhibitors. Such inhibitors are active by the intravenous route in primates but still lack of good oral activity 1.

Discovery
To investigate whether peptides related to the renin prosegment were able to inhibit renin activity, Evin et al., synthesized four peptides having the following structures: Arg-Ile-Pro-OMe, butyloxycarbonyl(Boc)-Leu-Lys-Lys-Met-Pro-OMe, Boc-Arg-Ile-Pro-Leu-Lys-Lys-Met-Pro-OMe, and Boc-Glu-Arg-Ile-Pro-Leu-Lys-Lys-Met-Pro-OMe (corresponding to amino acids 12-14, 15-19, 12-19, and 11-19, respectively, of the renin prosegment). All four peptides were found to inhibit the activity of pure mouse submaxillary renin on a porcine synthetic tetra-decapeptide in vitro 2.
However, peptidic renin inhibitors have been found to be poorly absorbed across the intestine or rapidly eliminated by the liver and have been reported to have oral bioavailabilities of less than 2%. A peptide-based renin inhibitor, A-72517 (molecular mass of 7 kDa) with considerable oral bioavailability, was devised and reported by HD Kleinert et al., in 1992. This inhibitor had oral bioavailabilities of 8, 24, 32, and 53% in the monkey, rat, ferret, and dog, respectively 3.

Structural Characteristics
On the basis of the minimal octapeptide sequence of the renin substrate, a series of peptides was synthesized containing (3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine) or (3S, 4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) at the P1P1' position. Some of these peptides also contained Nin-formyltryptophan at the P5, P3, or P3' position. Renin-inhibitory potency varied over a wide range (from inactive to IC50 = 3 nM). Potency was reduced by at least 10-fold when the peptide was shortened by two residues at either the amino or carboxy terminus. The AHPPA-containing inhibitors were several-fold less potent than the statine-containing inhibitors. Analysis of models for the three-dimensional structure of inhibitors at the active site of human renin suggests that the diminished potency of the AHPPA peptides in comparison with the statine-containing peptides was caused by a shift in the peptide backbone due to a steric conflict between the phenyl ring of the AHPPA residue and the S1 subsite. The importance of the side chain and the 3(S)-hydroxyl group of the statine residue was demonstrated by substituting 5-aminovaleric acid for a dipeptide unit at the P1P1' position, which resulted in a peptide devoid of renin-inhibitory activity. Substitutions of other basic amino acids for histidine at the P2 position caused a great loss in potency, possibly due to disruption of a hydrogen bond as suggested by molecular modeling. Studies on the plasma renins of four nonhuman species suggest that the isoleucine-histidine segment at the P2'P3' position is important to defining the human specificity of the substrate4.

Mode of Action
Renin inhibitors interfere with the first, rate-limiting step in the synthesis of angiotensin II by binding directly to the highly specific enzyme, renin. This approach may represent a more focused alternative to angiotensin-converting enzyme inhibitor therapy with an improved side-effect profile 5.

Functions
Renin inhibitors may offer an exciting new therapeutic means of blocking the actions of the renin-angiotensin-aldosterone system. Renin inhibitors given parenterally safely lower blood pressure in patients with essential hypertension and improve the hemodynamic profile of patients with congestive heart failure. Under conditions of salt limitation, normal subjects show increases in renal plasma flow during infusion of renin inhibitors. The systemic and renal hemodynamic responses to renin inhibition are accompanied by suppression of plasma renin activity, plasma angiotensin II and plasma aldosterone levels 5

References
1. Corvol P, Menard J (1989). Renin inhibition: immunological procedures and renin inhibitor peptides. Fundam Clin Pharmacol., 3(4):347-362.
2. Evin G, Devin J, Castro B, Menard J, Corvol P (1984). Synthesis of peptides related to the prosegment of mouse submaxillary gland renin precursor: an approach to renin inhibitors. PNAS., 81(1): 48–52.
3. Kleinert HD, Rosenberg SH, Baker WR, Stein HH, Klinghofer V, Barlow J, Spina K, Polakowski J, Kovar P, Cohen J (1992). Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy. Science, 257(5078):1940-1943.
4. Hui KY, Carlson WD, Bernatowicz MS, Haber E (1987). Analysis of structure-activity relationships in renin substrate analogue inhibitory peptides. J Med-Chem., 30(8): 1287-1295.
5. Kleinert HD (1996). Hemodynamic Effects of Renin Inhibitors. Am J Nephrol., 16:252-260.