Diversity-oriented synthesis; a challenge for synthetic chemists

Organic and Biomolecular Chemistry

Volumn 1, Issue 22, 2003, Pages 3867-3870

  Spring, David R ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AMINES; CARBOXYLIC ACIDS; CATALYSIS; DRUG PRODUCTS; MOLECULES; STEREOCHEMISTRY;

BIOLOGICAL PROBES; COMBINATORIAL CHEMISTRY; DIVERSITY-ORIENTED SYNTHESIS; SYNTHETIC REAGENTS;

SYNTHESIS (CHEMICAL);

EID: 0344515366     PISSN: 14770520     EISSN: None     Source Type: Journal    
DOI: 10.1039/b310752n     Document Type: Article

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24. There are many reasons for this trend, for example, the drug discovery process has become much more expensive ($231 million in 1990 to $897 million in 2000; a 388% increase); and although investment in pharmaceutical research and development has also increased dramatically, it has not increased as much as drug discovery costs ($10 billion in 1990 to >$25 billion in 2000; a 250% increase). The Tufts Center for the Study of Drug Development, News Release: 13 May 2003: http://csdd.tufts.edu/NewsEvents/ $231 million in 1990 is equivalent to $318 million in year 2000 dollars.
25. Large pharmaceutical companies have proprietary compound collections that they use for lead generation; many of the small molecules originate from previous medicinal chemistry projects and contain a high proportion of certain compound classes, sometimes called "privileged structures", such as benzodiazepines; thus, maximal structural diversity is inhibited.
26. Several companies (http://www.warr.com/ombichem.html#1) now sell discrete small molecule collections, and, although the molecules are structurally diverse, they tend to be low molecular weight (around 350 Da) and they rarely contain stereocentres.
27. Natural products are small molecules from the environment, synthesised by biosynthetic pathways and tend not to utilise as much chemical diversity available to a chemist, e.g. silicon atoms. Most natural products identified to date were isolated by assay-linked purification, singling out the most biologically active compounds. Natural products do show a high degree of structural diversity, but they are often mixtures (making it difficult to identify the active constituent), they are often isolated in low abundance, they are very costly to develop and they are often so structurally complex that chemical derivitisation is challenging synthetically.
28. See: http://www.ipi.com/.