References and notes

Geysen, H.M., Meloen, R.H., and Barteling, S.J., Use of peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid, Proc. Natl. Acad. Sci. U.S.A., 1984, 81(13), 3998. 2. Houghten, R.A., General method for the rapid solid-phase synthesis of large numbers of peptides specificity of antigen-antibody interaction at the level of individual amino acids, Proc. Natl. Acad. Sci. U.S.A., 1985, 82(15), 5131. 3. Merrifield, R.B., Solid phase peptide synthesis. I. The...

Case 1 Endothelin Converting Enzyme ECE1 Inhibitors

Hoffmann-La Roche Ltd. reported a solid-phase synthesis of 1,2,4-triazoles linked to a 4-mercaptopyrrolidine core as endothelin converting enzyme (ECE) inhibitors. ECE-1 is one of the two known homologs of the Zn-endopeptidase endothelin converting enzyme (ECE). ECE interacts with big-ET, cleaving and releasing endothelin-1 (ET-1), a 21-amino-acid peptide found in high plasma levels in people with hypertension, congestive heart failure, and pulmonary hypertension...

References

Gelmann, EP Robert-Guroff, M. Richardson, E. Kalyanaraman, V.S. Mann, D. Sidhu, G.D. Stahl, R.E. Zolla-Pazner, S. Leibowitch, J. and Popovic, M. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science, 1983, 220, 865-867. 2. Barre-Sinoussi, F. Chermann, J.C. Rey, F. Nugeyre, M.T. Chamaret, S. Gruest, J. Dauguet, C. Axler-Blin, C. Vezinet-Brun, F. Rouzioux, C. Rozenbaum, W. and Montagnier, L. Isolation of a T-lymphotropic retrovirus...

Case Study I Indoloquinolizinones 221 Origin of the Indoloquinolizinone Lead

In the early stages of this project, leads were identified by focused screening of a limited set of compounds that were either identified by molecular modeling or were members of a collection of compounds designed to exemplify a diverse set of molecular scaffolds. Initially, compounds were assayed by detection of the displacement of ZipA185.328 from the immobilized C-terminal 16 amino acid fragment of the FtsZ protein by surface plasmon resonance (SPR) 18 . Later on, as a new assay became...

Case 4 Ras Farnesyl Transferase Inhibitors

Saha et al.51 at Johnson & Johnson reported the solid-phase synthesis of triazole-based Ras farnesyl transferase inhibitors. Farnesyl transferase (FTase) is a zinc metalloenzyme that catalyzes the binding of a farnesyl group to the thiol of a cysteine residue of several proteins involved in cell signaling. The Ras oncogene protein contains a tetrapeptide sequence known as the CAAX motif that, upon farnesylation, promotes Ras translocation to the internal cell membrane. It has been determined...

Case 7 Tissue Factor Factor VIIa TFVIIa Complex Inhibitors

Parlow et al.46 at Pharmacia Corporation reported the structure-base design and polymer-assisted solution-phase synthesis of pyrazinones as selective small-molecule inhibitors of the tissue factor factor VIIa (TF VIIa) complex. The coagulation cascade involves several proteins that are activated at certain points in the coagulation pathway and form active complexes that, in turn, proteolytically activate other targets, ultimately generating the formation of thrombin (IIa) and a fibrin clot....

Antifungals

Kundu et al.10 at the Central Drug Research Institute in India published a classic study of using a positional scanning combinatorial chemistry peptide approach for the optimization of hexapeptides as antifungal agents. Screening a peptide collection against Candida albicans (Ca) and Cryptococcus neoformansa (Cn), the hexapeptide His-D-Trp-D-Phe-Phe-D-Phe-Lys-NH2 (compound 8) was identified as a hit with IC50 29.6 pM and MIC 6.81 pM, respectively. For this study it was decided to keep the...

Case 4 HRV 3CP Inhibitors

A Reich et al.42 at Pfizer Global R amp D-La Jolla Agouron Pharmaceuticals reported a study on the structure-based design of benzamide-based inhibitors of the human rhinovirus 3C protease HRV 3CP , particularly the HRV-14 3CP serotype. To design non-peptide inhibitors, the authors used the crystal structure of HRV-14 3CP co-crystallized with a peptide aldehyde. Analysis of the crystal structure led the authors to propose that 3-formylbenzamide would provide a scaffold where the aldehyde would...

Scheme

8.3.6 Generation of Library from Scaffold ii The second library based on lupeol involved the generation of compounds by derivatizing II with a variety of isocyanates, amino acids aromatic acids, and aromatic aldehydes and led to the synthesis of structurally diverse derivatives 6, 7, and 8 Scheme 8.5 . A library of 48 compounds was generated in parallel format using automation with 8 compounds represented by 6, 32 compounds represented by 7, and 8 compounds represented by 8. SCHEME 8.5 Reagents...

Case Study

8.3.1 Lead Optimization Studies with a Natural Product Lupeol Natural products play an important role in drug discovery, and many approved therapeutics as well as drug candidates have been derived from natural sources. They also represent promising scaffolds for diversification by using combinatorial techniques, as they have been selected by nature for their ability to undergo transformations in a three-dimensional space. Library construction around such scaffolds thus has the potential for...