Merck

Chemistry challenges in lead optimization: silicon isosteres in drug discovery.

Drug discovery today (2003-06-25)
Graham A Showell, John S Mills
RESUMO

During the lead optimization phase of drug discovery projects, the factors contributing to subsequent failure might include poor portfolio decision-making and a sub-optimal intellectual property (IP) position. The pharmaceutical industry has an ongoing need for new, safe medicines with a genuine biomedical benefit, a clean IP position and commercial viability. Inherent drug-like properties and chemical tractability are also essential for the smooth development of such agents. The introduction of bioisosteres, to improve the properties of a molecule and obtain new classes of compounds without prior art in the patent literature, is a key strategy used by medicinal chemists during the lead optimization process. Sila-substitution (C/Si exchange) of existing drugs is an approach to search for new drug-like candidates that have beneficial biological properties and a clear IP position. Some of the fundamental differences between carbon and silicon can lead to marked alterations in the physicochemical and biological properties of the silicon-containing analogues and the resulting benefits can be exploited in the drug design process.

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Silicon, powder, −60 mesh, 99.998% trace metals basis
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Silicon, pieces, 99.95% trace metals basis
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Silicon, powder, −325 mesh, 99% trace metals basis
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Silicon, sputtering target, diam. × thickness 2.00 in. × 0.25 in., 99.999% trace metals basis
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Silicon, nanopowder, <100 nm particle size (TEM), ≥98% trace metals basis
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Silicon, wafer (single side polished), <111>, N-type, contains no dopant, diam. × thickness 3 in. × 0.5 mm
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Silicon, wafer, <111>, P-type, contains boron as dopant, diam. × thickness 2 in. × 0.3 mm
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Silicon, wafer (single side polished), <100>, N-type, contains phosphorus as dopant, diam. × thickness 2 in. × 0.5 mm
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Silicon, wafer (single side polished), <100>, N-type, contains no dopant, diam. × thickness 3 in. × 0.5 mm
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Silicon, wafer (single side polished), <100>, P-type, contains boron as dopant, diam. × thickness 3 in. × 0.5 mm
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Silicon, wafer (single side polished), <111>, P-type, contains boron as dopant, diam. × thickness 3 in. × 0.5 mm
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Silicon, wafer (single side polished), <100>, N-type, contains no dopant, diam. × thickness 2 in. × 0.5 mm
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Silicon, wafer (single side polished), contains phosphorus as dopant, <111>, N-type, diam. × thickness 2 in. × 0.5 mm
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Silicon, wafer (single side polished), <111>, N-type, contains no dopant, diam. × thickness 2 in. × 0.5 mm
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Silicon, wafer (single side polished), <100>, P-type, contains boron as dopant, diam. × thickness 2 in. × 0.5 mm