Side activities, selective optimization

Wermuth CG. (2004) Selective optimization of side activities Another way for drug discovery. /. Med. Chem. 47 1303-1314. 

In theory, a drug with poor target specificity can be modified to enhance the side effect and decrease the original effect. This process is called selective optimization of side activities (SOSA). A significant advantage to SOSA is that the molecules, now considered hits for their secondary activity, have already been studied in clinical trials. The oral... 

Wermuth, C. Selective Optimization of Side Activities Another Way for Drug Discovery. J. Med. Chem. 2004, 47, 1303-1314. 

The SOSA approach (SOSA = Selective Optimization of Side Activities) represents an original alternative to high-throughput screening (HTS) [29-31]. SOSA consists of two steps ... 

A new strategy in drug discovery, the selective optimization of side activities (the SOSA approach), has been formulated by Camille Wermuth [17,18 cf. Chapter I—1], In this approach, minor side activities of active compounds serve as the starting point for structural variations, ultimately to obtain analogues that now have the former side effect as their main activity. In this manner, nanomolar acetylcholinesterase (AChE) inhibitors as well as nanomolar muscarinic M, receptor and 5-HT3 receptor ligands could be derived from the antidepressant minaprine [17,18],... 

The commercial bioconversion process employs the enzyme nitrile hydratase, which catalyzes the same reaction as the chemical process (Figure 31.15). The bioconversion process was introduced using wild-type cells of Rhodococcus or Pseudomonas, which were grown under selective conditions for optimal enzyme induction and repression of unwanted side activities. These biocatalysts are now replaced with recombinant cells expressing nitrile hydratase. The process consists of growing and immobilizing the whole cell biocatalyst and then reacting them with aqueous acrylonitrile, which is fed incrementally. When the reaction is complete the biocatalyst is recovered and the acrylamide solution is used as is. The bioconversion process runs at 10°C compared to 70°C for the copper-catalyzed process, is able to convert 100 percent of the acrylonitrile fed compared to 80 percent and achieves 50 percent concentration... 

The industrial point of view of catalyst characterization is different. Here the main interest is to optimize or produce an active, selective, stable and mechanically robust catalyst. In order to accomplish this, tools are needed which identify those structural properties that discriminate efficient from less efficient catalysts. In principle, all spectroscopic information that helps to achieve this is welcome. Empirical relations between the factors that govern catalyst composition, particle size and shape, and pore dimensions on one side, and catalytic performance on the other can be extremely useful in developing catalysts. 

Selective optimization of side activities as a way for drug discovery 04JMC1303. 

Unlike aspirin, this compound is reported to selectively acetylate the COX-2 serine residue and selectively inactivate COX-2. The I bulky heptynyl side-chain was optimized for I CCX2 selectivity in this SAR study and the I selective inhibition reported must be related I to the differences in active site or binding I pocket size, similar to the strategy for creating mary other selective inhibitors from modifica-I tions cf COX-1 inhibitors. 

Wermuth, C. G. Selective optimization of side activities the SOSA approach. Drug Discov. Today 2006, 11, 160-164. 

Ravichandran, V., Jain, P.K., and Agrawal, R.K (2007) Discovery of a new drug from old drug an overview on selective optimization of side activities. Journal of Pharmaceutical Research, 6, 178-184. 

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