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

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

doi:10.1021/acsmedchemlett.9b00369

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

ACS Med Chem Lett. 2020 Jan 24;11(10):1848-1854. doi: 10.1021/acsmedchemlett.9b00369. eCollection 2020 Oct 8.

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
² Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.

Abstract

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.