Renin inhibitors transition state analogs

The strategy of designing saquinavir was based on the transition-state mimetic concept, an approach that has been used successfully in the design of potent inhibitors of renin and other aspartic proteases [10]. From the variety of nonscissile transition-state analogs of a dipeptide, the hydroxyethylamine mimetic was selected because it most readily accommodates the amino acid moiety characteristic of the Phe-Pro and Tyr-Pro cleavage sequence of the... 

There is also great similarity between aspartic proteinases in terms of interactions with the transition-state analog inhibitors at the catalytic center. The catalytic aspartyl side chains and the inhibitor hydroxyl group are essentially superimposable in both renin complexes. The isostere C-OH bonds lie at identical positions when the structures of inhibitor complexes of several aspartic proteinases are superposed, in spite of the differences in the sequence and secondary structure. Most of the complex array of hydrogen bonds found in endothiapepsin complexes are formed in renin with the exception of that to the threonine or serine at 218, which is replaced by alanine in human renin. The similarity can be extended to all other pepsin-like aspartic proteinases and even to the retroviral proteinases [44,45]. This implies that the recognition of the transition state is conserved in evolution, and the mechanisms of this divergent group of proteinases must be very similar. 

B. Weidmann, Renin inhibitors, from transition state analogs and peptide mimetics to blood pressure lowering drugs, Chimia 1991, 45, 367-376. 

Thaisrivongs, S., Pals, D. T., Kroll, L. T., Turner, S. R., Han, F. S. Renin inhibitors. Design of angiotensinogen transition-state analogs containing novel (2R,3R,4R,5S)-5-amino-3,4-dihydroxy-2-isopropyl-7-methyloctanoic acid. J. Med. Chem. 1987, 30, 976-982. 

Rahuel, J., Priestle, J.P., Griitter, M.G. The crystal structures of recombinant glycosylated human renin alone and in complex with a transition-state analog inhibitor. J. Struct. Biol. 1991, 107, 227-236. 

Hydroxyethylene dipeptidc isosteres 35, which are of interest as transition state analogs, e.g., in renin inhibitors where they replace the scissile dipeptide unit (Leu-Val) of angiotensinogen, the natural substrate of renin, can be obtained from optically active acid 32 via iodolactoniza-tion in several steps. The synthesis of 32 is achieved using an Ireland - Claisen rearrangement as the key step which allows complete control of the three stereogenic centers44. For a stereocontrolled synthesis of peptide bond isosteres via Claisen rearrangements see also ref 448. 

These ideas, then, became the strategy for the design for numerous peptoids resembling known renin substrates. The scissile dipeptide was replaced with nonscissile statine and analogous amino acids such as 4-amino-5-cyclohexyl-3-hydoxypentanoic acid (ACHPA) and fluorostatinone to act as presumed transition-state analogs and to become potent renin inhibitors. 

The rationale applied in miniaturizing renin inhibitors to achieve clinically useful compounds by eliminating their protein nature and increasing inhibitory potency has, of course, wider ramifications. Judicious use of bioisosteric replacements and the relevancy of the transition-state analogy concept can also be applied with similar success to polypeptide neurotransmitters. 

Allen MC, Fuhrer W, Tuck B et al (1989) Renin inhibitors. Synthesis of transition-state analog inhibitors containing phosphoms acid derivatives at the scissile bond. J Med Chem 32 1652-1661... 

Patel DV, Rielly-Gauvin K, Ryono DE (1990) Preparation of peptidic a-hydtoxy phosphonates a new class of transition state analog renin inhibitors. Tetrahedron Lett 31 5587-5590... 

Intensive work worldwide on the design of renin inhibitors has yielded several classes of potent compounds. Most of these inhibitors are transition-state mimetics of the P -P scissile bond (Fig. 2) combined with peptide residues or analogues thereof [1], Much work has been focused on the minimization of the peptide character of renin inhibitors to overcome the drawbacks of substrate-analogous peptides, such as the instability towards enzymatic cleavage, biliary excretion, and low oral bioavailability. In the course of our studies on renin inhibitors at Roche, we synthesized a series of mimetics incorporating the P4-P3 binding elements [2, 3]. 

To study its mode of inhibition, we prepared several derivatives and measured their kinetics of inhibition. Both N-acetyl-statine and N-acetyl-alanyl-statine are competitive inhibitors for pepsin with values of 1.2 X lO M and 5.65 x 10 M, respectively. The value for N-acetyl-valyl-statine is 4.8 x 10 M. These statyl derivatives, therefore, are very strong inhibitors. The value for N-acetyl-statine is 600-fold smaller than that of its structural analog N-acetyl-leucine. The derivative which contains two statyl residues in a tetrapeptide exhibits inhibitory properties which approach those of pepstatin itself. Other acid proteases, human pepsin, human gastricsin, renin, cathepsin D, the acid protease from R. chinensis and bovine chymosin, also are inhibited by pepstatin and its derivatives. We suggest that the statyl residue is responsible for the unusual inhibitory capability of pepstatin and that statine is an analog of the previously proposed transition state for catalysis by pepsin and other acid proteases. 

Renin inhibition analogs Transition state inhibitors 326/1993... 

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