Pyrazolopyridines as potent PDE4B inhibitors: 5-Heterocycle SAR

Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.

Several series of pyrazolo[3,4-b]pyridine-5-heterocycles have been identified as potent inhibitors of PDE4B. Molecular modelling and X-ray crystallography on early analogues 7a–f and 10a–f led to the design of pyrazolo[3,4-b]pyridine-5-oxazole 16, which shows sub-nM potency against PDE4B. The crystal structure of 16 bound to PDE4B is also described.Figure optionsDownload as PowerPoint slide