Undesirable functionalities

Chemists and biologists have long known that certain chemical moieties are likely to produce false positives in biochemical assays because of their chemical reactivity [86]. Software filters are now routinely used at Vertex [24, 87] and other companies to flag compounds containing functional groups known empirically to contribute to reactivity, insolubility, toxicity, or poor ADME. Table 18.4 lists examples of such undesirable functional groups. 

Several large CROs have expanded their services into related markets such as contract product detailing, patient billing services and specialty pharmaceutical product development, manufacturing, and sales. The later situation can present a conflict of interest, if their own products are potentially competitive with the sponsor product candidates. Being both a CRO and a specialty pharmaceutical firm is awkward and represents an undesirable function in the contracting business. 

Hit follow-up consideration was accounted for via two filters to remove undesirable functional groups and to include molecules with a desirable functional group that would act as chemistry handles to enhance compound elaboration. These filters were derived from extended discussion with medicinal chemists. A total of 12 undesirable functional group sets were created and collectively used as a negative filter ... 

The system must be so designed that it cannot initiate an undesired function due to failure or to operator error. A failure in the higher levels of hierarchy must not degrade the elements in the lower levels. Some of the usual means of maintaining a secure system are by the use of ... 

In addition to physical properties, substructure-based filters can be applied to reduce further the number of molecules, for instance molecules with undesirable functionality for example, reactive or toxic groups can be removed and molecules with particular features (or atoms) can be actively selected. There may be particular functionality that it is desirable to avoid due to assay format, such as fluorophores in fluorescence-based approaches. Structural features for these inclusion and exclusion criteria can be readily formulated using SMILES-based procedures and this type of substructure-based compound selection technique can also be employed in the generation of focused sets of fragment molecules. 

An extensive range of in-house filters was applied to remove toxic, reactive and undesirable functionality. This set of filters has been built up based on years of experience with HTS screening and medicinal chemistry optimisation of hits to leads. A special focus was made... 

Once identified, these functional groups can be optionally excluded from future compound acquisitions or library designs unless a competing interest encourages their use. A report on the compound acquisition process at Novartis discusses how compounds are prioritized or eliminated for acquisition based on similarity to the historical collection, as well as physicochemical properties and undesirable functionality. Many of the same themes are presented in other reports on compound selection." ... 

Looking at Exhibit 13.2, we see that some functions are desired, some are insufficient, and some are undesired. Real estate commissions, for example, are an undesired function because they do not represent the ideal innovation and because they add signihcant and unnecessary cost to the process. 

Although spectroscopic analysis of resins does not lead to a quantitative determination of the loading, spectroscopic techniques can be very useful for the characterization of resins, as well as for the identification of possible undesired functional groups arising from incomplete reactions. 

Maximum allowable concentrations (MACs) are the maximum airborne concentrations that can be justified consistent with the objective of maintaining unimpaired health or comfort of workers or both. The criteria on which the standard is established are the avoidance of (1) undesirable changes in body structures or biochemistry, (2) undesirable functional reactions that may have no discernible effects on health, and (3) irritation or other adverse sensory effects. 

Functional group filters are applied to exclude from a chemical database those structures that possess undesired functionalities. These can be structures having more than one aldehyde group, structures containing metals, reactive alkyl halides, peroxides, carbazides. 

Now, the word fragment is beginning to make a dominant appearance. In diverse instances, smaller molecular entities derived from an important and complex macromolecule are found to have similar biochemical functions as the prominent parent, sometimes displaying one of the parent s several (desirable and undesirable) functions. 

Chains with undesired functionality from termination by combination or disproportionation cannot be totally avoided. Tn attempts to prepare a monofunctional polymer, any termination by combination will give rise to a difunctional impurity. Similarly, when a difunctional polymer is required, termination by disproportionation will yield a monofunetional impurity, fhe amount of termination by radical-radical reactions can be minimized by using the lowest practical rate of initiation (and of polymerization). Computer modeling has been used as a means of predicting the sources of chain ends during polymerization and examining their dependence on reaction conditions (Section... 

THIS SUBROUTINE IS CALLED TO CLEAR AWAY ANY UNDESIRABLE FUNCTIONALITY. ..ALPHA TO A KETONE ON THE RING... 

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