Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2009

Dolle, Roland E.; Bourdonnec, Bertrand Le; Worm, Karin; Morales, Guillermo A.; Thomas, Craig J.; Zhang, Wei

doi:10.1021/cc100128w

Cited by 86 publications

(38 citation statements)

References 374 publications

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“…From some 1495 papers, ca. 32 700 compounds were indexed with "preparation" in CAPlus (via SciFinder [42] [metals, unusual isotopes, and commercially available molecules removed]). From these, a total of 13 194 compounds fell within our 200-360 molecular weight range of which 5267 compounds satisfied lead-like LogP limits (i.e.…”

Section: Analysis Of Synthetic Methodologiesmentioning

confidence: 99%

“…Our final method of literature analysis made use of the annual survey of chemical library synthesis by Dolle and colleagues [43] in the Journal of Combinatorial Chemistry which provides a valuable snapshot of synthetic chemistry as it is currently applied to array and library construction (i.e. the application of robust chemistries).…”

Section: Analysis Of Synthetic Methodologiesmentioning

confidence: 99%

“…Tables 7-10 of ref. [43]) were visually inspected for lead-likeness. A total of 87 arrays with high scaffold molecular weight and/or undesirable chemotype were readily discarded, as it was clear the array would be unable to meet our definition of leadlikeness.…”

Section: Analysis Of Synthetic Methodologiesmentioning

confidence: 99%

“…A total of 87 arrays with high scaffold molecular weight and/or undesirable chemotype were readily discarded, as it was clear the array would be unable to meet our definition of leadlikeness. The references for the remaining 109 libraries were inspected and the products for each (as indexed in SciFinder) [42] extracted and analyzed for lead-likeness as described above. Over half the arrays (61) still occupied nonlead-like space entirely (see Table S5, Supporting Information).…”

Section: Analysis Of Synthetic Methodologiesmentioning

confidence: 99%

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Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

2012

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The pharmaceutical industry remains solely reliant on synthetic chemistry methodology to prepare compounds for small-molecule drug discovery programmes. The importance of the physicochemical properties of these molecules in determining their success in drug development is now well understood but we present here data suggesting that much synthetic methodology is unintentionally predisposed to producing molecules with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger numbers of compounds from array techniques are prepared. To address this issue we describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of molecules used to develop new medicines.

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Section: Analysis Of Synthetic Methodologiesmentioning

confidence: 99%

Section: Analysis Of Synthetic Methodologiesmentioning

confidence: 99%

Section: Analysis Of Synthetic Methodologiesmentioning

confidence: 99%

Section: Analysis Of Synthetic Methodologiesmentioning

confidence: 99%

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Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

2012

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“…In this context, combinatorial chemistry emerged as the fastest way to generate a large number of candidate compounds (5,6). However, early practices of large library synthesis and screening unveiled that the large number alone is not sufficient for increased hit rates and the structural diversity within the library may be important.…”

mentioning

confidence: 99%

Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity

Cruz

Wang²,

Kibbie

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The endothelium plays a critical role in promoting inflammation in cardiovascular disease and other chronic inflammatory conditions, and many small-molecule screens have sought to identify agents that prevent endothelial cell activation. Conversely, an augmented immune response can be protective against microbial pathogens and in cancer immunotherapy. Yet, small-molecule screens to identify agents that induce endothelial cell activation have not been reported. In this regard, a bioassay was developed that identifies activated endothelium by its capacity to trigger macrophage inflammatory protein 1 beta from primary monocytes. Subsequently, a 642-compound library of 39 distinctive scaffolds generated by a diversity-oriented synthesis based on the nucleophilic phosphine catalysis was screened for small molecules that activated the endothelium. Among the active compounds identified, the major classes were synthesized through the sequence of phosphine-catalyzed annulation, Tebbe reaction, Diels–Alder reaction, and in some cases, hydrolysis. Ninety-six analogs of one particular class of compounds, octahydro-1,6-naphthyridin-4-ones, were efficiently prepared by a solid-phase split-and-pool technique and by solution phase analog synthesis. Structure-function analysis combined with transcriptional profiling of active and inactive octahydro-1,6-naphthyridin-4-one analogs identified inflammatory gene networks induced exclusively by the active compound. The identification of a family of chemical probes that augment innate immunity through endothelial cell activation provides a framework for understanding gene networks involved in endothelial inflammation as well as the development of novel endothelium-driven immunotherapeutic agents.

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Parallel Chemistry in the 21^st Century

Long

2012

CP Pharmacology

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The tool chest of techniques, methodologies, and equipment for conducting parallel chemistry is larger than ever before. Improvements in the laboratory and developments in computational chemistry have enabled compound library design at the desks of medicinal chemists. This unit includes a brief background in combinatorial/parallel synthesis chemistry, along with a discussion of evolving technologies for both solid- and solution-phase chemistry. In addition, there are discussions on designing compound libraries, acquisition/procurement of compounds and/or reagents, the chemistry and equipment used for chemical production, purification, sample handling, and data analysis.

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Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2009

Cited by 86 publications

References 374 publications

Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity

Parallel Chemistry in the 21^st Century

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Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2009

Cited by 86 publications

References 374 publications

Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity

Parallel Chemistry in the 21st Century

Contact Info

Product

Resources

About

Parallel Chemistry in the 21^st Century