Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors

Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-α production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.

Graphical abstractA series of pyrazolo[3,4-b]pyridine-5-carboxamides has been identified as potent inhibitors of PDE4. The SAR has been explored and these studies have highlighted compound 20a which shows good potency, selectivity and rat PK suitable for oral dosing. The crystal structure of 20a bound to PDE4B is also described.Figure optionsDownload full-size imageDownload as PowerPoint slide