Phosphodiesterase inhibitors. Part 5: hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration

Koji Ochiai; Satoshi Takita; Akihiko Kojima; Tomohiko Eiraku; Kazuhiko Iwase; Tetsuya Kishi; Akira Ohinata; Yuichi Yageta; Tokutaro Yasue; David R Adams; Yasushi Kohno

doi:10.1016/j.bmcl.2012.08.121

Phosphodiesterase inhibitors. Part 5: hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration

Bioorg Med Chem Lett. 2013 Jan 1;23(1):375-81. doi: 10.1016/j.bmcl.2012.08.121. Epub 2012 Nov 9.

Authors

Koji Ochiai¹, Satoshi Takita, Akihiko Kojima, Tomohiko Eiraku, Kazuhiko Iwase, Tetsuya Kishi, Akira Ohinata, Yuichi Yageta, Tokutaro Yasue, David R Adams, Yasushi Kohno

Affiliation

¹ Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.

PMID: 23200255
DOI: 10.1016/j.bmcl.2012.08.121

Abstract

(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.

MeSH terms

Administration, Inhalation
Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / pharmacology
Bronchoalveolar Lavage Fluid / cytology
Bronchodilator Agents / chemical synthesis
Bronchodilator Agents / chemistry*
Bronchodilator Agents / pharmacology
Cyclic Nucleotide Phosphodiesterases, Type 3 / chemistry
Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism
Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
Drug Design
Leukocytes / drug effects
Phosphodiesterase 3 Inhibitors / chemical synthesis
Phosphodiesterase 3 Inhibitors / chemistry*
Phosphodiesterase 3 Inhibitors / pharmacology
Phosphodiesterase 4 Inhibitors / chemical synthesis
Phosphodiesterase 4 Inhibitors / chemistry*
Phosphodiesterase 4 Inhibitors / pharmacology
Protein Binding
Pyridazines / chemistry
Pyridines / chemistry
Rats
Structure-Activity Relationship

Substances

6-(7-methoxy-2-trifluoromethylpyrazolo(1,5-a)pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone
Anti-Inflammatory Agents
Bronchodilator Agents
Phosphodiesterase 3 Inhibitors
Phosphodiesterase 4 Inhibitors
Pyridazines
Pyridines
Cyclic Nucleotide Phosphodiesterases, Type 3
Cyclic Nucleotide Phosphodiesterases, Type 4