Directed combinatorial libraries

Because deuterium is heavier than hydrogen, the carbon-deuterium bond has a lower vibrational frequency than the carbon-hydrogen bond. This difference in frequency makes the carbon-deuterium bond slower to react. 

If bond breaking occurs during the rate-determining step of the reaction, then the overall reaction will be slowed by the replacement of hydrogen with deuterium. This is an example of a kinetic isotope effect. The use of deuterium as a bioisostere to manipulate rates of metabolism is a fairly new idea in drug discovery. If SD-254 successfully reaches the market, additional deuterated drugs will almost certainly be advanced into clinical trials. 

The term combinatorial chemistry typically evokes images of huge libraries of molecules with members of 100,000 and even more. This type of large library is ideal for lead discovery, a situation in which a medicinal chemist is trying to cast a diverse structural net to search for activity. The lead optimization process is more specialized. The basic skeleton of the eventual candidate may already be known. Only the ideal substituents on the pharmacophore remain in question. While lead discovery and lead optimization are very different tasks, combinatorial chemistry can effectively play a role in both processes. 

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Fig. 18.3 Variation-based strategies. Left The SHAPES Linking Library [11] consists of drug-like scaffolds connected by linkers that are amenable to combinatorial chemistry (dashed line). Hits are followed up by synthesizing a combinatorial library in which the scaffolds are systematically varied. Center Directed Combinatorial Librari es [12] are comprised of scaffolds containing multiple sites for substituents. Hits are followed up by...

Gehlhaar, D. K., Bouzida, D., and Rejto, P. A. (1999) Reduced dimensionality in ligand-protein structure prediction covalent inhibitors of serine proteases and design of site-directed combinatorial libraries. ACS Symposium Series 719, 292-311. 

Zhou, J. Z. (2008) Structure-directed combinatorial library design. Curr Opin Chem Biol 12, 379-385. 

A second problem for Hansch analysis and any other predictive method is combinatorial chemistry. As methods in combinatorial chemistry continue to be refined and advanced, directed combinatorial libraries constructed around the scaffold of a lead have become a more standard practice. The availability of hundreds of lead analogues greatly diminishes the potential contribution from a Hansch equation. Why predict a structure s activity when one can make a library of essentially all interesting analogues, screen the library, and know the activity for certain ... 

Pharmacophore fingerprints generated from complementary site points can be used to direct combinatorial library design and to investigate selectivity. An example of the pharmacophore fingerprinting method for selectivity studies has been validated (37a,b) in studies of three closely related serine proteases thrombin, Factor Xa, and trypsin. Site points were... 

HTS data as well as virtual screening can guide and direct the design of combinatorial libraries. A genetic algorithm (GA) can be applied to the generation of combinatorial libraries [18. The number of compounds accessible by combinatorial synthesis often exceeds the number of compounds which can be syiithcsii ed... 

The head-to-tail-coupling reactions described above are potentially useful in the design of dynamic combinatorial libraries. Features of these reactions include the rapid and reversible formation of carbon-carbon bonds, multifunctional ene-imine building blocks, and formation of stereo centers upon ene-imine linkage. Support for template-directed synthesis utilizing ene-imine building blocks is the formation of a poly ene-imine species that could recognize 3 -GGA-5 sequences of DNA.48 It is noteworthy that some polyene-imines are helical and could form a triple helix with DNA. 

Combinatorial libraries have been prepared as discrete compounds or as mixtures with each approach having obvious advantages and disadvantages. Establishing the presence and purity of library members is straightforward when discrete compounds are synthesized. In addition, biological evaluation of discrete compounds directly corre-... 

Wipf et al. <2005OL4483> elaborated a new metathesis method including ring opening in order to generate dynamic combinatorial libraries. The transformation is shown in Scheme 12. The essence of this method is the recognition that an equilibrium takes place with 93 and an aldehyde in aqueous conditions at pH 4 in a phosphate buffer. With the help of this transformation, a series of new R2-substituted products 94 - not available via direct ring closure - have been synthesized. 

There has been significant advancement in the applications of NMR to the development of small-molecule pharmaceutical products. For example, advances in NMR automation (e.g., flow-injection analysis) and directly coupled methods (e.g., LC-MS-NMR analysis) have made analysis and characterization of small-molecule drugs much easier.23 25 These improvements have helped chemists to develop and characterize small-molecule combinatorial libraries and to screen for active compounds.4 6 It is likely some of these techniques can also be used in biopharmaceutical product development. 

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