Escape from Flatland. Lovering, Bikker and Humblet.
The authors surveyed all of the compounds with MW<1000 disclosed since 1980 (in the GVKBIO database – remember that?) and compared and contrasted them with the subset of molecules had made it to each of the clinical phases and to registration as drugs. They were particularly concerned with understanding whether adding unsaturation into molecules improves their medicinal chemistry properties and assessed this by computing the fraction of carbon atoms that are sp3 hybridised and whether the molecule is chiral or not. As you can see, their analysis suggests that at each progressive stage of the drug development process, the average fraction of sp3 carbons increases and (not shown) the proportion that are chiral also increases but not in quite as clear a way. This paper provides a challenge to chemists to find new methods that don’t naturally increase the number of flat atoms in the molecule (as amide couplings and the various palladium catalysed aryl couplings).
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