Target selectivity

The Jamieson paper reports the results of a number of studies, some successful, others not. Failures can be ascribed to the difficulties encountered in log P control. The first evident trouble concerns the choice of the lipophilicity descriptor many prefer log P, but this choice is questionable as has been outlined by Lombardo (see Chapter 16). Secondly, variations in lipophilicity profile influence not only hERG activity, but also target selectivity and also ADMET properties. Lipophilicity is a bulk property and its modification can involve different moieties of the molecules. Once the chemical modulation has been designed, but before moving to the bench, the research group should predict the consequences of this change on each step of the drug s action, but unfortunately this is not always done. 

SB-366791 (18) emerged from screening an in-house library as a potent competitive inhibitor of both hTRPVl and rTRPVl, endowed with superior target selectivity compared to capsazepine [84]. Structure-activity relationships of SB-366791 remain to be reported. 

Different from the use of ordinal insecticides, this disruption method has high target selectivity and, as would be desired, ensures the survival of natural enemies. The sex pheromone, which shows no toxicity to mammals, is an ideal insect-behavior regulator (IBR). Table 8 shows the application areas of main mating disruptants for lepidopteran insects. In addition to the use of the synthetic pheromone of P. gossypiella in large cotton fields, many disruptants are... 

Use of previously identified coding polymorphisms influencing the activity of the target => Selection of individuals in order to increase the chances of seeing a therapeutic response... 

Saunders AM et al. The role of apolipo-protein E in Alzheimer s disease phar-macogenomics target selection. Biochim Biophys Acta 2000 1502 85-94. 

S. Tanimoto, S. Sakai, S. Matsumura, D. Takahashi, and K. Toshima, Target-selective photo-degradation of HIV-1 protease by a fullerene-sugar hybrid, Chem. Commun. (2008) 5767-5769. 

Cell adhesion molecules (CAMs) play critical roles in all facets of nervous system development and maintenance. Important phenomena in which CAMs are involved include initial formation of the neural tube and the neural crest, migration of all neurons and glial cells, axonal outgrowth and guidance, target selection, synaptic stabilization and plasticity, myelination and nerve regeneration after injury (see Chs 4,24,28-30 and 53). Adhesion molecules interact with each other and with nonadhesive cell-surface and/or cytoplasmic molecules, and, in the two... 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

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