Combinatorial chemistry peptidomimetics

Nefzi, a., Dooley, C., Ostresh, ).M., and Houghten, R.A. Combinatorial chemistry from peptides and peptidomimetics to small organic and heterocyclic compounds. Bioorg. Med. Chem. Lett. 1998, 8, 2395-2398. 

The first applications of solid phase synthesis were to peptides, hence it is no surprise that there have been several reports of HRMAS studies of peptide systems attached to a support. One of the earliest reports of HRMAS in a supported sample was that of Wang-bound lysine, whose structure was determined by TOCSY and HMQC HRMAS NMR.38 More recently, HRMAS NMR has been used to identify several peptidomimetic inhibitors of hepatitis C virus NS3 protease while on the resin.79 However, it is perhaps a bit surprising that more has not been made of HRMAS in attacking problems of relevance to peptide synthesis, although most recent interest is moving that way. Combinatorial chemistry and solid phase organic chemistry has been a much more active area using HRMAS techniques. 

Given the extensive biology associated with peptides, it is not surprising that considerable effort has been devoted to the synthesis of peptidomimetics to overcome the unfavorable properties and therapeutic deficiencies of peptides. In particular, since the advent of solid-phase synthesis and, more recently, combinatorial chemistry, interest in peptido-mimetic design and preparation has exploded. In theory, the peptide chemist is only limited by their imagination in the novel modifications that can be tailored for synthetic peptide analogues. 

The first installment in this series (Volume 267, 1996) mostly covered peptide and peptidomimetic based research with just a few examples of small molecule libraries. In this volume we have compiled cutting-edge research in combinatorial chemistry, including divergent areas such as novel analytical techniques, microwave-assisted synthesis, novel linkers, and synthetic approaches in both solid-phase and polymer-assisted synthesis of peptides, small molecules, and heterocyclic systems, as well as the application of these technologies to optimize molecular properties of scientific and commercial interest. 

We summarize here the efforts to generate a virtual library of peptidomimetic pentameric inhibitors of the HIV PR, derived from ritonavir (Figure 4.1), developed by the Abbott Laboratories [18,19] using computer-assisted combinatorial chemistry methods [20]. 

The third group of alliances focuses on lead optimization. Here, a particular lead is known, such as a small peptide and it is desired to optimize the activity of that lead. In the case of peptides this could be accomplished through phage display and/or peptidomimetic combinatorial chemistry. Companies involved in alliances of this type have proprietary technologies that enable them to generate usually small-molecule libraries built around particular molecular themes, for example, steroid cores. Examples include alliances of Ontogen, Dyax, ArQule, etc. 

The identification of peptidomimetics through combinatorial chemistry and high-throughput screening may negate the need to address the challenge of biopharmaceutical drag delivery. 

The design strategies employed to improve combinatorial chemistry have evolved considerably since the early days of peptide and peptidomimetic libraries. The main concern early was on the availability of suitable synthetic methods that could be applied to the synthesis of libraries of small molecules however, this early obstacle has been intensively addressed and at this point can be considered overcome (for examples of new methodology developed for library production see Ref 21). With the ability in hand to prepare many different types of molecules in a variety of formats, the current challenge is to decide what compounds to make. As a consequence, much attention is now focused on the definition and analysis of chemical diversity. 

As mentioned before, combinatorial chemistry, high-throughput screening, and analogous techniques have become powerful tools to promote drug discovery in peptidomimetic research. It is not the intention of this chapter to summarize all these methods, and excellent... 

A novel methodology employing aza-Payne rearrangement and OJ<[-intramolecular acyl transfer reactions was reported by Tamamura et for the synthesis of peptidomimetics containing hydroxyethylamine dipeptide isosteres (87). This method is also applicable for the synthesis of hydroxyethylamine dipeptide isosteres containing pseudopeptides and also for combinatorial chemistry using solid-phase techniques. 

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