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

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Hamblin JN, Angell TD, Ballantine SP, Cook CM, Cooper AW, Dawson J, Delves CJ, Jones PS, Lindvall M, Lucas FS, Mitchell CJ, Neu MY, Ranshaw LE, Solanke YE, Somers DO, Wiseman JO

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

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4237-41. doi: 10.1016/j.bmcl.2008.05.052. Epub 2008 May 17.

PubMed ID

18539455 [ View in PubMed

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Abstract

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-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
cAMP-specific 3',5'-cyclic phosphodiesterase 4B	Q07343	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide	cAMP-specific 3',5'-cyclic phosphodiesterase 4B	IC 50 (nM)	3.16	N/A	N/A	Details