Cyclic urea, HIV protease inhibitor

Figure 7.14 Cyclic urea HIV protease inhibitor incorporating an oxygen atom in place of a bound water molecule. (Reprinted with permission from Anderson, A.C. The process of structure-based drug design. Chem. Biol. 2003, 10, 19,1-191. copyright 2003, Elsevier.)...

A Scheme for the preparation of a series of cyclic urea HIV protease inhibitors containing alkynyl-tethered heterocycles in the P2 region includes hydrogenation with LiAlH4 in THF in 60-80% yields (96BMCL797) (Schemes 83 and 84). 

Initially Kurup et al. [15] analyzed some series of aminoindazoles [79,80]. Later, a comprehensive comparative QSAR study on P2/P2 and Pi/Pj substituted symmetrical and non-symmetrical 3-aminoindazole cyclic urea HIV protease inhibitors (21) was performed [81]. The SAR data were taken from different papers [79,80,82-85]. Several QSAR models were developed for individual datasets. QSAR 16-18 were derived for the combined set [81]. 

Several molecular modeling studies using various 3D-QSAR techniques have been reported in the Uterature on cyclic urea HIV protease inhibitors. Most of them were based on a heterogeneous dataset taken from the work of different authors. Because of the nature of the dataset studied, it was difficult to group them in distinct classes however, an attempt has been made to organize the following discussion according to the previous subsection for comparison purposes. 

Flow chart showing the design of novel orally active HIV-1 protease inhibitor. (Figure adapted from Lam P K ]adhav, C E Eyermann, C N Hodge, Y Ru, L T Bacheler, ] L Meek, M ] Otto, M M Rayner, Y N V /ong, ang, P C Weber, D A Jackson, T R Sharpe and S Erickson-Viitanen 1994. Rational Design of Potent, able. Nonpeptide Cyclic Ureas as HIV Protease Inhibitors. Science 263 380-384.)... 

Lam PYS, Jadhav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek JL, Otto MJ, Rayner MM, Wong YN, Chang CH, Weber PC, Jackson DA, Sharpe TR, Erickson-Viitanen S. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 1994 263 380-4. 

Another significant work in this area entails the modeling of the activity of cyclic urea HIV-1 protease inhibitors using artificial neural networks <2006BMC280>. 

Tetrazole thioacetanilides 595 (HIV non-nucleoside reverse transcriptase inhibitors) <2006BML2748> and derivatives of cyclic ureas 596 (nonpeptide inhibitors of HIV protease) have been prepared <1998JME2019>. 

HIV-protease/inhibitor complexes have a molecular weight of approximately 22 kDa. Although NMR spectroscopy is well suited to determination of the structure of molecules in this size range, efforts to determine the solution structure of the complex were hampered by the fact that the protease undergoes rapid autocatalysis in solution. It required the development of potent inhibitors before NMR studies of the complex became feasible. The first solution structure of HIV-protease bound to the cyclic urea inhibitor DMP-323 (Fig. 25) was reported by Yamazaki in 1996.133 The protease exists as a homodimer. Each 99-residue monomer contains ten /3-strands and the dimer is stabilized by a four-stranded antiparallel /3-sheet formed by the N- and C-terminal strands of each monomer. The active site of the enzyme is formed at the interface, where each monomer contributes a catalytic triad (Asp25-Thr26-Gly27) that is... 

Lam, P.Y.S., et al. Rational design ofpotent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors, Science, 1994, 263, 380-384. 

Figure 15.38. Cyclic ureas as non-peptide HIV protease inhibitors.

Lam, P.Y.S. et al. Cyclic HIV protease inhibitors Synthesis, conformational analysis, P2/P2 structure-activity relationship, and molecular recognition of cyclic ureas. J. Med. Chem. 1996, 39, 3514-3525. 

Epoxides can be readily formed using the standard Mitsunobu reaction conditions. A recent example (88) from the literature is shown below. The reader is referred to the cited paper for additional examples. Bis-epoxides such as 89 were useful in the preparation of a series of cyclic urea based HIV protease inhibitors. 

Incorporation of the position of water molecules that are firmly bound to the protein can impart affinity and novelty to the designed ligand. A prime example is the design of a class of HIV protease cyclic urea inhibitors by DuPont scientists that incorporated a water molecule bound to both flaps of the enzyme into their ligand [32]. The crystal structure of the HIV protease-cyclic urea complex [32] shows the urea carbonyl oxygen substituting for the position of the water molecule. 

Many other non-peptide inhibitors of HIV protease (dihydropyrone, cyclic urea and sulphamide series of compounds) were obtained by modifications of random screening leads. Examples of these include a cyclic sulph-one derivative 147 and 148 (PNU-140690) that showed activity against a variety of HIV t)rpe 1... 

Burello E., Frecer V, Miertus S, Combinatorial design and focusing of library of cyclic urea inhibitors of aspartic protease of HIV-1, chem. Biochem. submitted. 

Amazaki TY, Hinck AP, Wang XY, Nicholson LK, Torchia DA, Wingfield P, Stahl SJ, Kaufman JD, Chang CH, Domaille PJ, Lam PY, Three-dimensional solution structure of the HIV-1 protease complexed with DMP323, a novel cyclic urea-type inhibitor, determined by nuclear magnetic resonance spectroscopy, Protein Sci., 5 495-506, 1996. 

---