Synthesis and SAR Studies of 1H‑Pyrrolo[2,3‑b]pyridine-2-carboxamides as Phosphodiesterase 4B (PDE4B) Inhibitors

Herein we report the synthesis, SAR, and biological evaluation of a series of 1H-pyrrolo­[2,3-b]­pyridine-2-carboxamide derivatives as selective and potent PDE4B inhibitors. Compound 11h is a PDE4B preferring inhibitor and exhibited acceptable in vitro ADME and significantly inhibited TNF-α release from macrophages exposed to pro-inflammatory stimuli (i.e., lipopolysaccharide and the synthetic bacterial lipopeptide Pam3Cys). In addition, 11h was selective against a panel of CNS receptors and represents an excellent lead for further optimization and preclinical testing in the setting of CNS diseases.