Fragments vs LTA4H: LipE in action

Three years ago we described the discovery of LYS006, an inhibitor of leukotriene A4 hydrolase (LTA4H) from Novartis currently in phase 2 clinical trials. Companies often pursue multiple chemical series for important targets, and in a recent J. Med. Chem. paper Gebhard Thoma and colleagues describe another fragment-derived lead against LTA4H.

 

A biochemical high-throughput screen yielded compound 2, which is quite potent for a fragment-sized molecule. However, despite good ligand efficiency, the LipE (or LLE) was less impressive due to the high lipophilicity of the fragment. (Note that throughout the paper LipE is calculated based on measured logD rather than logP.) A co-crystal structure revealed that it bound in a similar fashion to other previously characterized LTA4H inhibitors such as compound 1, derived from LYS006 and reported in a J. Med. Chem. paper last year. Adopting elements from these led eventually to compound 12, which though less potent was also much less lipophilic and more soluble while still remaining fragment-sized.

 

 

Continuing to borrow from the rich literature around this target, the researchers added a basic amine group to get to the very potent compound 14. This was metabolically unstable, but further optimization led to compound 3.

 

Compound 3 was profiled extensively in a battery of tests. In addition to good biochemical potency, it showed mid-nanomolar activity in a human whole blood assay and was also active in other assays, including a mouse arthritis model. Other attractive features included a clean profile against a plethora of off-targets, good oral bioavailability in mice, rats, and dogs, and a predicted human oral dose of 40 mg once daily. However, a two week toxicology study in rats and dogs was “slightly less favorable” than compound 1.

 

This is a lovely example of property and structure-guided drug design, and the researchers are refreshingly open about borrowing elements from other molecules, even from outside Novartis. Interestingly, a crystal structure of compound 3 bound to LTA4H revealed that while the overall binding mode was similar to compound 1, which contains the same left-hand portion, the pyrazole and pyridine rings rotated 180º to make different hydrogen-bond interactions. Another reminder that despite our leaps in predictive capability, molecules can still provide many surprises.