Here we describe the discovery and optimization of Piperidinopiperazines and  derivatives thereof as potent and selective inhibitors of Autotaxin (ATX) based on a high-throughput screening (HTS) campaign sampling our in-house compound collection. The compounds optimized subsequently to the Benzotriazole derivatives and characterized herein are potently inhibiting the PDE activity of ATX and also lowering the LPA levels in plasma significantly. X-ray protein crystallographic data demonstrated that these inhibitors bind to the LPC/LPA binding side with an important interaction to one of the Zn atoms. The SAR, optimization of physchem and pharmacokinetic properties as well as in vivo activity are also described.

Synthesis of potent and selective Autotaxin inhibitors

243rd National Meeting (2012)

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