Identification of 2,3-disubstituted pyridines as potent, orally active PDE4 inhibitors

Yoshihiro Kato; Motoji Kawasaki; Tomohiro Nigo; Shunya Nakamura; Akira Fusano; Yasuhiro Teranishi; Mari N Ito; Takaaki Sumiyoshi

doi:10.1016/j.bmc.2013.07.007

Identification of 2,3-disubstituted pyridines as potent, orally active PDE4 inhibitors

Bioorg Med Chem. 2013 Sep 15;21(18):5851-4. doi: 10.1016/j.bmc.2013.07.007. Epub 2013 Jul 14.

Authors

Yoshihiro Kato¹, Motoji Kawasaki, Tomohiro Nigo, Shunya Nakamura, Akira Fusano, Yasuhiro Teranishi, Mari N Ito, Takaaki Sumiyoshi

Affiliation

¹ Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, Suita, Osaka, Japan.

PMID: 23910988
DOI: 10.1016/j.bmc.2013.07.007

Abstract

A series of 2,3-disubstituted pyridines were synthesized and evaluated for their PDE4 inhibitory activity. We successfully modified undesirable cyano group of initial lead compound 2 to 4-pyridyl group with improvement of in vitro efficacy and optimized the position of nitrogen atoms in pyridine moiety and alkylene linker. The most potent compound showed significant efficacy in animal models of asthma and inflammation.

Keywords: 2,3-Disubstituted pyridine; Anti-inflammatory agent; PDE4 inhibitors; Phosphodiesterase 4; Structure–activity relationship.

MeSH terms

Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / therapeutic use
Asthma / chemically induced
Asthma / drug therapy
Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry*
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
Disease Models, Animal
Male
Mice
Phosphodiesterase 4 Inhibitors / chemical synthesis
Phosphodiesterase 4 Inhibitors / chemistry*
Phosphodiesterase 4 Inhibitors / therapeutic use
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / therapeutic use
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents
Phosphodiesterase 4 Inhibitors
Pyridines
Cyclic Nucleotide Phosphodiesterases, Type 4
pyridine