Parallel medicinal chemistry

Some aspects of this parallel drug design environment were evident in the pages of J. Med. Chem. in 2001, for example, leads from HTS of designed 

In fact, this is exactly the status achieved by 2001 with regard to oral absorption potential, as discussed in the next section. 

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Searle, Parallel Medicinal Chemistry, Monsanto Company,... 

The combination of alternative screening approaches, virtual screening, parallel medicinal chemistry in combination with an early profiling on the multitude of relevant compound properties will hopefully generate an improved basis for proper decisions about which promising lead series to take forward. 

Kattar SD et al (2009) Parallel medicinal chemistry approaches to selective HDAC1/HDAC2 inhibitor (SHI-1 2) optimization. Bioorg Med Chem Lett 19(4) 1168—1172... 

In the program that led to discovery of Xelzanj, initial hits were optimised using parallel medicinal chemistry. Thus, a novel multistep protocol based on reductive amination followed by SfjAr reaction was developed using commercially available cyclic ketones for quick exploration of the head group in the lead compound A. This led to identification of a key dimethyl... 

Figure 18.2 Impact of parallel medicinal chemistry in the discovery of Xelzanj (tofacitinib).

To illustrate how an effective monomer collection can be created, we will go through a case study. For this purpose, we will consider the Pfizer monomer collection and how it was created. The efforts at Pfizer have largely been focused on creating a monomer collection that facilitates the preparation of target molecules via parallel medicinal chemistry (PMC) approaches in chemically enabled design space the aim of this was to allow the rapid advancement of programs through their discovery cycle. 

As we have highlighted, the monomer collection is key for the successful utilisation of parallel medicinal chemistry (PMC) in drug discoveiy projects. Clearly, it is impossible to have access to all possible monomers (with less than 11 heavy atoms and MW of <200 and clogP<2.0) because the numbers run into the millions of compounds. A more systematic approach is to enrich the monomer collection available while at the same time... 

In recent years, parallel medicinal chemistry has undergone a substantial shift from being focused on large libraries to enable hit identification to more focused libraries enabling program advancement. This effort can be... 

At the same time, the continued development of innovative parallel medicinal chemistry protocols has allowed the targeting of ever more challenging target space. Many challenges remain but there can be little doubt that the approach is highly effective in delivering new lead series for medicinal chemistry projects. 

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

The discovery of this lead compound as a potent PDF inhibitor was a result of an integrated combinatorial and medicinal chemistry approach based on the proposed generic PDF inhibitor structure. This focused chemical library was designed by Chen et al. [79], and was prepared using solid-phase parallel synthesis in which 22 amines and 24 amino acids were used as building blocks, as outlined in Scheme 23. 

Combinatorial chemistry as described above, fraught with problems of expense, purity, compound identification, and storage have largely been supplanted in the modem medicinal chemistry laboratory by the more measured and reliable techniques broadly termed "parallel synthesis."... 

Mitscher, L.A. and Dutta, A., Combinatorial chemistry and multiple parallel synthesis, in Burger s Medicinal Chemistry and Drug Discovery, Abraham, D.J., Ed., 6th ed., Vol. 2, Drug Development, Wiley, New York, 2003. 

It was quickly realized that parallel synthesis techniques could be used to increase the efficiency of medicinal chemistry in this role [111]. Small optimization libraries were produced using parallel synthesis technologies and they took advantage of the ability... 

ADME models Structural biology Parallel synthesis Medicinal chemistry... 

Mitscher, Lester A., and Apurba Dutta. Combinatorial Chemistry and Multiple Parallel Synthesis, John Wiley fit Sons, Inc. Available online. URL http //media.wiley.eom/product data/excerpt/82/04713702/ 0471370282.pdf. Originally published in Burger s Medicinal Chemistry and Drug Discovery, edited by Donald J. Abraham. Vol. 2, Drug Discovery and Development. Hoboken, N.J. Wiley, 2003. 

Kansy M., Sermer, F. and Gubernator, K. (1998) Physicochemical High Throughput Screening Parallel Artificial Membrane Permeation Assay in the Description of Passive Absorption Processes. Journal of Medicinal Chemistry, 41, 1007-1010. 

Lazaro, E., Lowe, P.J., Briand, X. and faller, B. (2008) New approach to measure protein binding based on a parallel artificial membrane assay and human serum albumin. Journal of Medicinal Chemistry, 51, 2009-2017. 

Rajesh V. Devraj, Parallel Medicinal Combinatorial Chemistry Unit, Searle/Monsanto Life Sciences Company, 800 N. Lindbergh Blvd., St. Louis, MO 63167, USA... 

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