Huang Z, Dias R, Jones T, Liu S, Styhler A, Claveau D, Otu F, Ng K, Laliberte F, Zhang L, Goetghebeur P, Abraham W M, Macdonald D, Dubé D, Gallant M, Lacombe P, Girard Y, Young R N, Turner M J, Nicholson D W, Mancini J A
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada.
Biochem Pharmacol. 2007 Jun 15;73(12):1971-81. doi: 10.1016/j.bcp.2007.03.010. Epub 2007 Mar 16.
Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.
4型磷酸二酯酶（PDE4）抑制剂正在成为治疗多种慢性疾病（包括哮喘、慢性阻塞性肺疾病（COPD）和认知障碍）的新兴疗法。本研究描述了L-454,560的临床前特征，它是一种强效、竞争性且对PDE4A、4B和4D具有选择性的抑制剂，IC50值分别为1.6、0.5和1.2 nM。与西洛司特的排他性结合以及罗氟司特对PDE4全酶状态（Mg2+结合形式）的选择性结合不同，L-454,560与PDE4的脱辅基（无Mg2+）状态和全酶状态均能结合。L-454,560抑制PDE4的内在酶活性还能有效阻断全血中脂多糖（LPS）诱导的肿瘤坏死因子α（TNFα）生成（IC50 = 161 nM），并且与人全血中罗氟司特的活性相当。L-454,560的细胞因子抑制谱主要为Th1谱，对干扰素γ（IFNγ）有显著抑制作用，在高达1 μM时未检测到对白细胞介素13（IL-13）生成的抑制作用。还发现L-454,560在两种气道高反应性模型中有效，即卵清蛋白（OVA）致敏和激发的豚鼠模型以及蛔虫致敏绵羊模型。此外，L-454,560在改善Morris水迷宫位置延迟匹配（DMTP）版本中的表现方面也有效，其剂量与潜在呕吐无关。因此，L-454,560是一种新型PDE4抑制剂，其总体体内疗效至少与罗氟司特相当，明显优于西洛司特。
