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

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.
Koji Ochiai 1 Satoshi Takita Akihiko Kojima Tomohiko Eiraku Kazuhiko Iwase Tetsuya Kishi Akira Ohinata Yuichi Yageta Tokutaro Yasue David R Adams Yasushi Kohno
Affiliations

Affiliation

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

Figures
Products