Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Bioorg Med Chem Lett. 2013 Jan 1;23(1):375-81. doi: 10.1016/j.bmcl.2012.08.121. Epub 2012 Nov 9.
(-)-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.
（-）-6-（7-甲氧基-2-（三氟甲基）吡唑并[1,5-a]嘧啶-4-基）-5-甲基-4,5-二氢哒嗪-3（2H）-酮（KCA-1490）表现出适度的双重 PDE3/4 抑制活性，并有望成为一种联合支气管扩张/抗炎药物。哒嗪酮环的 N-烷基化显著增强了对 PDE4 的活性，但抑制了 PDE3 的抑制作用。在 N-烷基上添加 6-芳基-4,5-二氢哒嗪-3（2H）-酮延伸部分，有利于增强 PDE4 抑制活性和恢复有效 PDE3 抑制作用。核心和延伸中的两个二氢哒嗪酮环都可以被非手性的 4,4-二甲基吡唑酮取代，而核心吡唑并吡啶可以被等排的双环杂芳烃取代。这些修饰的组合提供了有效的双重 PDE3/4 抑制剂，可抑制体内组胺诱导的支气管收缩，并通过气管内给药表现出有希望的抗炎活性。
