molecules of the month


CNS-penetrant non-zinc binding ATX inhibitor

oral PK/PD and efficacy in inflamm. pain model

from phosphonic acid hit from S1P library

ACS Medicinal Chemistry Letters

Biogen Inc., Cambridge, US

1 min read

The Biogen compound BIO-32546 is a potent (IC50 = 1 nM), selective, oral, non-zinc-binding reversible autotaxin (ATX) inhibitor, and is an interesting example of a relevantly large brain-penetrant zwitterion. The molecule has a distinct structure from ATX inhibitors previously highlighted (e.g. Small Molecules of the Month May, Jul., Nov. 2020) and was derived from an phosphonic acid-containing inhibitor hit (28 nM) from a lipid mimetic chemical library. If your first reaction was that this molecule looks like an S1P modulator, you're not crazy - the chemical library was derived from Biogen's S1P program. Optimization was guided by cocrystal structures and the window against a hERG liability (surprising for an acid-containing molecule) was mitigated with introduction of a benzylic methyl group.…

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