3D fragments vs the histamine H1 receptor

Last month we highlighted a paper from Iwan de Esch and colleagues at Vrije Universiteit Amsterdam about assessing molecular shapeliness. In a new open-access RSC Med. Chem. paper, de Esch and colleagues use a small, shapely library to find and develop potent antagonists of the histamine H₁ receptor (H₁R).

 

The G protein-coupled receptor H₁R is one of four histamine receptors and the target for dozens of antihistamines used for allergic and inflammatory conditions. Thus, it’s well understood and a nice model system.

 

In 2013 we discussed how the de Esch group screened a library of 1010 fragments against several targets, including H₁R. In the new paper, the researchers built a smaller library of just 80 compounds designed to be more shapely, as assessed by Fsp³, plane of best fit (PBF), and principal moment of inertia (PMI). A screen against H₁R using a radioligand displacement assay at 10 and 30 µM yielded a single hit, compound 1a.

 

Compound 1a deviates slightly from the rule of three due to some unusual elements: an azide as a synthetic handle and a butyl moiety to make the compound less explosive. Trimming these features led to compound 3a, a rule-of-three compliant fragment that – while having lower affinity – mostly maintained ligand efficiency and improved lipophilic ligand efficiency (LLE). Fragment growing led to compounds 13a and 13k, and merging with previously reported molecules led to compound VUF26691, with low nanomolar affinity and picomolar antagonistic activity in a cell assay. Throughout the process the cis isomers generally had equal or better potency than the trans isomers, an empirical observation difficult to explain by modeling.

 

This is a nice fragment-to-lead story, and the researchers note that fewer than 40 compounds were synthesized in the journey from compound 3a to VUF26691. Interestingly though, compound 1a was the only hit from the 80 compounds tested, while the hit rate from the larger, flatter library screened in 2013 was nearly three-fold higher, at 3.6%. Although it’s difficult to extrapolate from n=1, the results are consistent with our post last year that more shapely libraries will likely have lower hit rates.

 

Still, this shapely hit makes for a neat scaffold, and if nothing else perhaps it will be easier to establish intellectual property.