Symmetric inhibitor

Hanessian and Devasthale, 1996] Hanessian, S., and Devasthale, P. Design and synthesis of novel, pseudo C2 symmetric inhibitors of HIV protease. Bioorg. Med. Chem. Lett. 6 (1996) 2201-2206... 

Erickson J, Neidhart DJ, VanDrie J, Kempf DJ, Wang XC, Norbeck DW et al. Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor com-plexed to HlV-1 protease. Science 1990 249 527-33. 

Fig. 6. A symmetrical inhibitor designed to fit the symmetrical HIV protease active site.

This compound, as well as the symmetric 37, was used in a series of microwave-heated aminocarbonylations and direct amide N-arylations, producing 12 compounds (six unsymmetric and six symmetric) with a two- or three-atom spacer between the aromatic moieties (Scheme 20) [80]. The best unsymmetric inhibitor had a Ki of 140 nM (43) and the best symmetric inhibitor 20 nM (44). 

These compounds showed much improved activity against pro-tease-resistant strains of HIV as compared with DMP450. Both 8 and 9 exhibited good oral bioavailability (60%) and a sustained plasma half-life (3-8 hours). One additional advantage of the nonsymmetrical inhibitors was their reduced molecular weight compared with polar symmetrical inhibitors. Plasma levels of cyclic ureas dropped abrupdy when the molecular weight of a compound exceeded 620 Da. 

Dawson RMC, Elliott DC, Elliott WH, Jones KM. Data for Biochemical Research, 3rd edition. 1986. Clarendon Press, Oxford. Miller MJ, Braccolino DS, Cleary DG, Ream JE, Walker MC, Sikorski JA. EPSP synthase inhibitor design iv New aromatic substrate analogs and symmetrical inhibitors containing novel 3-phosphate mimics. Bioorg. Med. Chem. Lett. 1994 4 2605-2608. Boudreau MA, Vederas JC. Synthesis and biological evaluation of nucleoside dicarboxylates as potential mimics of nucleoside diphosphates. Org. Biomol. Chem. 2007 5 627-635. 

Both (31)(Fig. 10.9b) and (32) (Fig. 10.11) bind to the HIV-P active site asymmetrically. However, after the X-ray studies of crystalline HIV-P apoenzyme revealed it to be a symmetrical dimer, C2 symmetric inhibitors were designed to take advantage of this structural feature (Fig. 10.12). Both alcohol diamines and diol diamines were examined. For example, the C2 symmetric compound (33) (A-77003) was synthesized at Abbott and entered clinical trials as an antiviral agent for intravenous treatment of AIDS (100). 

Figure 10.12. Design principle for C2 symmetric inhibitors of HIV-P and the related hydroxyethylene diamine scaffold.

Inhibitors of cathepsin K illustrate the principles developed to inhibit this class of enzyme. This enzyme sequence was detected in 1994 by sequencing of human DNA for the human genome project (126).Cathepsin K was found to be inhibited by leupeptin (63) and by compound (64), which surprisingly binds "backwards" to the active site (Fig. 15.30). A hypothesis to develop symmetrical inhibitors of cathepsin K derived from the superposition of both aldehydes on the carbonyl carbon this led to the diamino ketone TSA (65). The diamino ketone moiety seems to work in several classes of cysteine proteases (127). 

As had been predicted prior to the determination of the X-ray structure, the proteinase assembles its catalytic machinery using a C2 symmetric homodimer (as opposed to a monomer in renin). The symmetrical nature of the enzyme suggested that C2 symmetric inhibitors might be effective. The X-ray structure also revealed the presence of an ordered water molecule bound to two of the carbonyl groups of the inhibitor. Displacement of such a water molecule with an inhibitor should, theoretically, lead to greatly enhanced activity. This theory was exploited with a class of cyclic inhibitors that mimicked the interactions of the water molecule with functionality within the inhibitor leading to highly potent and compact inhibitors, e.g., XM-323 (see Scheme 9) (15). 

Figure 10. Stereoview of the X-ray crystal structure of the symmetric inhibitor A-74704 (magenta) bound in the HFV-l protease (cleft region, cyan) [82], HzOSOl is shown in green.

The symmetrical arrangement of enzymes into homodimers or tetramers defines the active site of the enzyme in a highly symmetrical fashion. Thus, symmetrical inhibitors will correspond generally to the binding site of the enzyme. 

FIGURE 18.40 (a) Interaction of the bisubstrate inhibitor RM65 (magenta) and SAM (green) with the PRMTl binding site. The symmetrical inhibitor... 

RT and HIV PR is capable of reducing the viral load in blood patients. These enzymes, which exist respectively as a heterodimer and a homodimer for HIV RT and HTV PR, are well-characterized more than 170 structures of HIV PR and its complexes with various inhibitors have been solved by protein crystallography techniques. Thus, a dipalmitoylated derivative of 2,7-naphthalene disulfonic acid demonstrated micromolar activity for both fflV-1 and HIV-2 RT (Fig. 16.14). Symmetrical nature of HTV PR was used in the search for novel anti-HTV drugs that would embody the predicted characteristic of the active site. The design of inhibitors of HIV PR has led to symmetrical compounds, which can be divided into two groups (1) pseudosymmetrical compounds, like derivatives A 74704 ° and L 700,417 which contain asymmetric atoms in close proximity to the inhibitor two-fold axis (2) fully Ca-symmetrical inhibitors like the cyclic urea and the diol derivatives (Fig. 16.14). 

Ca-symmetric or pseudo-Ca-symmetric inhibitors and cyclic urea derivatives... 

Dreyer, G.B. et al. A symmetric inhibitor binds HIV-1 protease asymmetrically. Biochemistry 1993, 32, 937-947. 

Using the C2-symmetric inhibitor A-74704 3 (29, Kj = 4.5 nM) bound to HlV-1 protease as a guide, Randad et al. of the National Cancer Institute-Frederick Cancer Research and Development Center designed six-membered cyclic urea inhibitors (30). Using SYBYL for modeling and energy minimiza-... 

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