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

Vadukoot, Anish
K.; Sharma, Swagat; Aretz, Christopher D.; Kumar, Sushil; Gautam, Nagsen; Alnouti, Yazen; Aldrich, Amy L.; Heim, Cortney E.; Kielian, Tammy; Hopkins, Corey R.

doi:10.1021/acsmedchemlett.9b00369.s001

ml9b00369_si_001.pdf (641.69 kB)

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

journal contribution

posted on 2020-02-03, 16:24 authored by Anish K. Vadukoot, Swagat Sharma, Christopher D. Aretz, Sushil Kumar, Nagsen Gautam, Yazen Alnouti, Amy L. Aldrich, Cortney E. Heim, Tammy Kielian, Corey R. Hopkins

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.