Renin transition state analogues

Blundell TL, Cooper J, Foundling SI, Jones DM, Atrash B, Szelke M. On the rational design of renin inhibitors X-ray studies of aspartic proteinases complexed with transition state analogues. Biochemistry 1987 26 5585-5590. 

Fig. 11. Some transition state analogues incorporated into inhibitors of renin and of HIV protease.

The peptidic a-hydroxyl phosphonates present a promising and structurally unique class of transition-state analogue inhibitors of proteolytic enzymes and make the first disclosure of their application in preparing inhibitors of human renin. 

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

Characterization of HIV-1 protease as a member of the aspartic acid protease family provided the rationale for most of the efforts to design inhibitors (Kohl et al, 1988 Krausslich et al., 1988 Navia et al., 1989 Pearl and Taylor, 1987). Previous efforts to develop therapeutically useful inhibitors of the mechanistically related enzyme renin had demonstrated that potent inhibitors could be prepared by replacing the scissile amide bond of a substrate analogue with a nonhydrolyzable isostere to mimic the tetrahedral intermediate or transition state involved in amide hydrolysis (Greenlee, 1990). Although several dipeptide isosteres have been used to successfully generate highly potent HIV-1 protease inhibitors, a relatively small number have resulted in compounds that reached clinical development. 

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]. 

---