Macrocycles hold tremendous promise for modulating the most challenging and neglected targets in the pharmaceutical domain. Unfortunately, an unintended consequence of the widespread application of Lipinski's Rule of 5 to the development of small molecule screening collections has been that these collections now primarily consist of low molecular weight heteroaromatic structures with rigid geometries and lack more complex molecules such as macrocycles. The pharmaceutical industry has been effective at exploiting the macrocycle structural class through the use of natural products and cyclic peptides, but these structures come with their own liabilities. Non-peptidic synthetic macrocycles remain an under-utilized structural class likely due to synthetic challenges and concerns about the difficulty of rapidly addressing structure activity relationships through medicinal chemistry.The Broad Institute has taken advantage of the utility of diversity oriented synthesis to construct a large collection of non-peptidic macrocycles. Using readily available and scalable starting materials, our group has synthesized over 20,000 novel macrocycles, each possessing between 2 and 5 stereocenters. A unique feature of the collection is that for each compound all stereoisomeric permutations are available, providing valuable information about stereo-structure activity relationships of hits from primary screening data. Recent successes to emerge from screening this collection will be discussed, as well as how the synthetic design of the libraries has contributed to the ease of hit to lead efforts�addressing one of the major liabilities of performing medicinal chemistry on this class of compounds.

Diversity oriented synthesis provides synthetically tractable macrocycles as part of a small molecule screening collection

248th National Meeting (2014)

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