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

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

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18 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1848-1854
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00369
State	Published - Oct 8 2020

Keywords

1H-Pyrrolo[2,3- b]pyridine-2-carboxamide
PDE4B
phosphodiesterase 4
scaffold hopping

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.9b00369

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

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.",

keywords = "1H-Pyrrolo[2,3- b]pyridine-2-carboxamide, PDE4B, phosphodiesterase 4, scaffold hopping",

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AU - Vadukoot, Anish K.

AU - Sharma, Swagat

AU - Aretz, Christopher D.

AU - Kumar, Sushil

AU - Gautam, Nagsen

AU - Alnouti, Yazen

AU - Aldrich, Amy L.

AU - Heim, Cortney E.

AU - Kielian, Tammy

AU - Hopkins, Corey R.

PY - 2020/10/8

Y1 - 2020/10/8

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AB - 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.

KW - 1H-Pyrrolo[2,3- b]pyridine-2-carboxamide

KW - PDE4B

KW - phosphodiesterase 4

KW - scaffold hopping

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

Abstract

Keywords

ASJC Scopus subject areas

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