Nonpeptidic inhibitor

DesJarlais RL, Seibel GL, Kuntz ID, Furth PS, Alvarez JC, Ortiz de Montellano PR, DeCamp DL, Babd LM, Craik CS. Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease. Proc Natl Acad Sci USA 1990 87 6644-8. 

Rutenber E, Fauman EB, Keenan RJ, Ortiz de Montellano PR, Meng E, Kuntz ID, DeCamp DL, Salto R, Rose JR, Craik CS, Stroud RM. Structure of a nonpeptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design. J Biol Chem 1993 268 15343-6... 

Hajduk PJ, Sheppard G, Nettesheim DG, Olejniczak ET, Shuker SB, Meadows RP, Steinman DH, Carrera GM, Marcotte PA, Severin J, Walter K, Smith H, Gubbins E, Simmer R, Holzman TF, Morgan DW, Davidsen SK, Summers JB, Fesik SW. Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR. J Am Chem Soc 1997 119 5818-5827. 

Yehia NAM, Antuch W, Beck B, Hess S, Schauer Vukasinovic V, Ahnstetter M, Eurer P, Herdtweck E, Domling A (2004) Novel nonpeptidic inhibitors of HIV-1 protease obtained via a new multicomponent chemistry strategy. Bioorg Med Chem Lett 14 3121-3125... 

Tirofiban is a synthetic, nonpeptide inhibitor of glycoprotein-(GP)-receptors. Tirofiban has a rapid onset and short duration of action after intravenous administration. Coagulation parameters turn to normal 4-8 hours after the drug is withdrawn. Tirofiban in combination with heparin and aspirin is indicated in the management of patients with unstable angina or non-Q-wave myocardial infarction. 

Due to their substantial size and peptidic nature, inhibitors from this class were not suitable for clinical application. Nevertheless, the structural information derived from many crystal structures of peptidic inhibitors bound to the HIV PR active site was critical for subsequent modeling and design of the next generation of peptidomimetic and nonpeptidic inhibitors of HIV PR. 

Saquinavir, despite its distinct peptidomimetic character is a very potent inhibitor of HIV PR with an inhibition constant of 0.9 nMand an antiviral IC50 in vitro of 0.020 iM[ 10]. Although it suffers from a low oral bioavailability (5-10% in humans), it became an important starting point for the design of second generation, less-or nonpeptidic inhibitors. Saquinavir became the first HIV PR inhibitor approved by the FDA for treatment of AIDS. 

Most inhibitors in this latter class were initially discovered by screening natural-products libraries or by structurebased de novo design. The most interesting examples of the nonpeptidic inhibitors from this group are the independently discovered but structurally... 

Reich SH, Melnick M, Davies JF, Appelt K, Lewis KK, Fuhry MA, Pino M, Trippe AJ, Nguyen D, Dawson H, Wu B-W, Musick L, Kosa M, Kahil D, Webber S, Gehlhaar DK, Andrada D, Shetty B. Protein structure-based design of potent, orally bioavailable, nonpeptide inhibitors of human immunodeficiency virus protease. Proc. Natl. Acad. Sci. 1995 92 3298-3302. 

To determine if higher plants produce nonpeptide inhibitors of Candida-secreted aspartic proteases (SAPS), it was necessary to develop a sensitive and specific primary bioassay suitable for screening large numbers of plant extracts, to have access to a unique and diverse plant collection to evaluate for the presence of inhibitors, and to have available purified recombinant Saps for use in a secondary assay to corroborate any observed activity. 

The azepane (3)-3-methyl-l- 3-oxo-l-[2-(3-pyridin-2-ylphenyl)ethenoyl]azepane 4-ylcarbamoyl butylamide is a potent nonpeptide inhibitor of rat cathepsin K (and thus of potential value in the control of osteoclast-mediated bone resorption) <2002MI746>, and an N-substituted azepane-isatin derivative was reported to be a nonpeptide inhibitor of caspase 3 <2001JME2015> another N-substituted azepane-indole derivative was shown to act as an estrogen <2001JME1654>. 

Another system based on an SEC pre-column was employed by Earley and Tini for the analysis of a nonpeptidic inhibitor of human leukocyte elastase as part of a drug discovery project (13). The analytical column used here was octadecylsilane, although the authors commented that, depending on the particular application, any stationary phase could be used as the analytical column. In their application, a fraction of the effluent from the SEC column was transferred to the analytical column by the use of a C18 collection column that served to pre-concentrate and focus the analytes. They noted that frequent solvent flushing was required to avoid build-up of impurities on the collection column. A chromatogram obtained from a 50 p.L plasma standard injection is shown in Figure 15.6. This separation provides an excellent... 

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>. 

D. L. DeCamp, L. M. Babe, and C. S. Craik, Proc. Natl. Acad. Sci. U.S.A. 87, 6644 (1990). Structure-Based Design of Nonpeptide Inhibitors Specific for the Human Immunodeficiency Virus 1 Protease. 

In the second example, we summarize our efforts to design highly focused virtual library subset of nonpeptidic inhibitors of HIV PR, using structure-based computational approach [20]. 

The work described by Deadman et al. [100] considered a subset of the above set of thrombin inhibitors. A training set of 16 homologous nonpeptide inhibitors whose conformations had been generated in continuum solvent (MacroModel) and clustered into conformational families (XCluster) was regressed against this pharmacophore so as to obtain a 3D-QSAR mode. 

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