Fragments vs hematopoietic prostaglandin D2 synthase

Prostaglandins are modified fatty acids involved in myriad biological processes. The enzyme hematopoietic prostaglandin D2 synthase (H-PGDS) converts prostaglandin H2 to prostaglandin D2 and is a potential target for inflammatory disorders. In an article just published online in MedChemComm, Gordon Saxty and co-workers at Astex and collaborators at GlaxoSmithKline describe how they used fragment-based methods to develop orally available inhibitors of this enzyme.

The researchers started by screening their fragment library against crystals of H-PGDS, resulting in 76 fragment hits, some of which were quite potent (sub-micromolar). Two are described in the paper, with most of the focus being on Fragment 6, which wasn’t the most potent but did produce an interesting conformational shift in the protein. Also, although H-PGDS typically binds lipophilic molecules, the researchers were intrigued to observe that the polar pyrazole moiety made two hydrogen bonds to the protein.

Structure-guided optimization of Fragment 6 led to Fragment 8 with a modest improvement in affinity, and fragment growing led to Compound 9, with a satisfying 400-fold boost in affinity. In one of those “nice to have” problems, this compound was actually too hydrophilic (ClogP < 1), but increasing the lipophilicity slightly led to Compound 10 (AT24111 / GSK2696124A), which has low nanomolar potency and oral bioavailability in both mice and rats. The compound also blocked prostaglandin D2 production in mice when dosed orally.

This is a concise but elegant paper, and it is impressive that the researchers managed to maintain or improve ligand efficiency throughout optimization. Of course, all the molecules contain a pyrazole moiety, which is a privileged pharmacophore for kinases, so it will be important to carefully assess selectivity.

Finally, you may recall that Astex was acquired by Otsuka earlier this year. Whenever an acquisition happens there is always the worry that the acquired company will be decimated or shuttered entirely. Happily, this doesn’t seem to be the case here. In fact, Astex actually seems to be expanding: I recently saw a full page job advertisement from them in Nature, and as of this morning their website lists 9 openings, with several in research. Hopefully the honeymoon lasts a long time!