Chem. Pharm. Bull. 53(10) 1305—1309 (2005)

hypertension and heart failure, especially because of their high specificity for angiotensinogen. In the past a large number of peptidic renin inhibitors were designed and synthesized. Unfortunately, a majority of them showed poor oral absorption and rapid biliary uptake. The above limitations may result from the substrate-like structure of the synthesized inhibitors. Therefore, other structures of renin inhibitors were also sought. Investigation of the crystal structure of human renin revealed that it is composed of two b-sheet domains and the cleft between them. This cleft extends over seven or eight residues of the substrate (S4–S3 ). 1—3) Studies of the conformational structure of the cleft showed that the S3–S1 subsites forming a hydrophobic pocket constitute a large hydrophobic cavity. Other subsites (S1 –S3 ) are contained in the cleft, but their pockets are not well defined. On the basis of these findings, inhibitors of a new type were designed and synthesized. The peptide fragment P3–P1 was replaced by a moderately hydrophobic moiety enclosing an aliphatic or alicyclic fragment showing affinity to the S1 and aromatic fragment with affinity to the S3 subsites. 3) It was recently determined that respective substituents of the aromatic portion of the molecule are able strongly to enhance the binding affinity to renin and the selectivity of the inhibitor. This moiety was directly linked to the C-terminus of the transition state analog containing a hydroxyl moiety. The analog with a cyclohexyl substituent, used in numerous inhibitors, seemed especially worthy of note. This type of inhibitor did not contain residues at positions P2 and P3 , but rather an amide aliphatic chain. The inhibitors obtained showed high in vitro affinity for renin and good bioavailability, and they were effective in lowering blood pressure in primates. Aliskiren seems a very promising of new type compound. It is a highly potent and selective non-peptidic renin inhibitor in vitro and in vivo. Indeed, it contains only one peptide bond and is deprived of the P4–P1 fragment characteristic of the peptide inhibitors. Inhibiting of renin activity is due to hydrogen binding of the hydroxyl groups of the transition state analog to the catalytically active Asp 32 and Asp 215 residues of renin. Also, derivatives of 3,4-substituted piperidine, which bind to a new enzyme active site conformation, are very potent renin inhibitors of a new type characterized by a complete non-peptidic structure. This conformation suggests that aspartic proteinase active sites have latent conformational flexibility. The most promising are two inhibitors with good pharmacodynamic and pharmacokinetic properties. However, there must be more possibilities for producing effective drugs free from side effects. Our intention is search for new active inhibitors with simple structure, good bioavailability, inexpensive and easy synthesis. We intend to reach this purpose by coupling non-peptidic fragments with good affinity to some regions of the substrate. We previously obtained several in vitro active renin peptidic inhibitors. Between them are compounds with pseudodipeptidic units at P1–P1 as well at P2 –P3 positions and activity in vitro in the limits of 10 5 M/l. Other previously obtained inhibitors with eAhx ethylamide or eAhxisoamylamide also at the P2 –P3 positions showed inhibitory activity at a concentration of 10 5 M/l. On the other hand, substitution of only an isoamylamide group at this position produces an inactive compound. Substitution of the eAhx-amide fragment appeared equally effective as a pseudodipeptidic unit, but was obtained more easily and much more cheaply. But the presence of a pseudodipeptidic unit, ideally with an alicyclic ring, is necessary at the P1–P1 position. All things considered, we designed a series of inhibit ors enclosing three different pseudodipeptidic units at the P3–P2 positions. We wanted to find the most effective one at this position. The units are in the successive compounds: (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA), (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta) and unnatural dipeptide Phe(4OMe)-MeLeu. All of them contain at the P1–P1 positions ACHPA, whose hydroxyl group is presumed to be bound to two Asp residues. Chains of all four inhibitors are lengthened at the C-terminus by linkage of e-aminohexanoic acid (eAhx) isoamylamide (Iaa). Chemistry The inhibitors (12, 19, 23, 29) as well as their intermediates were synthesized as shown in Schemata 1—4 (Fig. 2). Their structures are shown in Fig. 1. General October 2005 Notes Chem. Pharm. Bull. 53(10) 1305—1309 (2005) 1305