Small and simple, but novel and potent

Back in 2012 we wrote about GDB-17, a database of possible small molecules having up to 17 carbon, oxygen, nitrogen, sulfur, and halogen atoms, most of which have never been synthesized. Although novelty isn’t strictly necessary for fragments, as evidenced by the fact that 7-azaindole has given rise to three approved drugs, it’s certainly nice to have. In a new (open-access) J. Med. Chem. paper, Jürg Gertsch, Jean-Louis Reymond, and colleagues at the University of Bern synthesize fragments that had not been previously made and show that they are biologically active.

 

When you start drawing all possible small molecules you get lots of weird stuff, including an explosion of compounds containing multiple three- and four-membered rings, which may be difficult to make. The researchers wisely focused on “mono- and bicyclic ring systems containing only five-, six-, or seven-membered rings.” They further limited their search to molecules containing just carbon and one or two nitrogen atoms (as well as hydrogen, of course). Systematic enumeration led to 1139 scaffolds, ignoring stereochemistry, of which 680 had not been previously reported in PubChem. Out of these, three related scaffolds were chosen for investigation.

 

Computational retrosynthesis was used to devise routes to the three bicyclic scaffolds, and these were successfully synthesized, along with mono-benzylated versions, for a total of 14 molecules (including stereoisomers), all rule-of-three compliant. The online Polypharmacology Browser 2 (PPB2) was used to predict targets, and several monoamine transporters came up as potential hits. The molecules were tested against norepinephrine transporter (NET), dopamine transporter (DAT), serotonin transporter (SERT), and the σ-R1 receptor in radioligand displacement assays. None of the free diamines were active, but several of the benzylated compounds were, in particular compound 1a.

 

Compound 1a was initially made as a racemic mixture, and when the two enantiomers were resolved (R,R)-1a was found to be a mid-nanomolar inhibitor of NET while (S,S)-1a was 26-fold weaker. Compound (R,R)-1a was also a mid- to high nanomolar inhibitor of σ-R1, DAT, and SERT. Pharmacokinetic experiments in mice revealed that the molecule had poor oral bioavailability but remarkably high brain penetration and caused sedation. The researchers conducted additional mechanistic studies beyond the scope of this blog post and conclude that (R,R)-1a could be a lead for “neuropsychiatric disorders associated with monoamine dysregulation.”

 

There are several nice lessons in this paper. First, as we noted more than a decade ago, there is plenty of novelty at the bottom of chemical space. Moreover, and in contrast to our post last week, even small fragments can have high affinities. But novelty comes at a cost: synthesis of compound 2a required eight steps from an inexpensive starting material with an overall yield of just 9%, though this could certainly be optimized. Nonetheless, particularly for CNS-targeting drugs which usually need to be small in order to cross the blood brain barrier, the price might be worth paying.

 

Of course, even within this paper there are hundreds more scaffolds to look at than the three tested, and perhaps the researchers were lucky that their choices were biologically active. As computational methods continue to advance, it will be worthwhile turning them loose on GDB-17.