title: Chemistry challenges in lead optimization: silicon isosteres in drug discovery.
abstract: 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.
authors.affiliation: Amedis Pharmaceuticals Ltd., 162 Cambridge Science Park, Milton Road, UK. graham.showell@amedis-pharma.com
authors.forename: Graham A
authors.initials: GA
authors.lastname: Showell
authors.forename: John S
authors.initials: JS
authors.lastname: Mills
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000639:trends; D002986:Clinical Trials as Topic; D020650:Combinatorial Chemistry Techniques; D016208:Databases, Factual; D015195:Drug Design; D004345:Drug Industry / Q000639:trends; D006801:Humans; D018716:Molecular Mimicry; D015394:Molecular Structure; D017646:Organosilicon Compounds / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012825:Silicon / Q000737:chemistry*
chemical_list: D017646:Organosilicon Compounds; D004364:Pharmaceutical Preparations; D012825:Silicon