CDP 840 hydrochloride

CDP 840是IV型磷酸二酯酶（PDE4）的选择性抑制剂[1][2][3]，IC50值为0.007 μM[4]。

PDE4在炎症细胞如单核细胞和巨噬细胞中分布最为广泛[3]。PDE4是高亲和性的cAMP选择性同工酶。PDE4在哮喘病的几乎所有类型细胞中出现[2]。

CDP 840具有有效的对PDE4的抑制能力，对PDE4的不同同工酶的IC50值范围为2-30 nM。在杆状病毒细胞中表达有四种PDE4同工酶，即PDE4A、PDE4B、PDE4C和PDE4D。除PDE4C2外，CDP 840对PDE4无同工选择性。CDP 840对所有四种PDE4同工酶的峰值为约1.0。对所有四种PDE4同工酶，CDP 840是简单的竞争性抑制剂[5]。

在体内，在雄性Sprague-Dawley大鼠中，CDP 840（30 mg/kg）可分别增加海马和前额叶皮层中cAMP含量达145%和112%。CDP 840在10和30 mg/kg剂量下提高海马（分别为36和55%）和前额叶皮层（分别为32和60%）中cAMP响应元件结合蛋白（pCREB）的磷酸化。但这些剂量不影响cAMP响应元件结合蛋白（CREB）表达。CDP 840在30 mg/kg剂量下的重复处理可提高大鼠海马体中的细胞增殖，但这些细胞不能存活[6]。

参考文献：
[1].  T.R. Jones, M. McAuliffe, C.S. McFarlane, et al. Effects of a selective phosphodiesterase IV inhibitor (CDP-840) in a leukotriene-dependent non-human primate model of allergic asthma. Can. J. Physiol. Pharmacol., 1998, 76: 210-217.
[2].  Chun Li, Nathalie Chauret, Laird A. Trimble, et al. Investigation of the in vitro metabolism profile of a phosphodiesterase-IV inhibitor, CDP-840: leading to structural optimization. Drug Metabolism and Disposition, 2001, 29:232–241.
[3].  John E. Souness and Sudha Rao. Proposal for Pharmacologically Distinct Conformers of PDE4 Cyclic AMP Phosphodiesterases. Cell. Signal., 1997, 9(3/4):227-236.
[4].  Christopher Hulme, Gregory B. Poli, Fu-Chih Huang, et al. Quaternary substituted PDE4 inhibitors I: the synthesis and in vitro evaluation of a novel series of oxindoles. Bioorganic & Medicinal Chemistry Letters, 1998, 8:175-178.
[5].  M.J. Perry, J. O'Connell, C. Walker, et al. CDP840: a novel inhibitor of PDE-4. Cell Biochem. Biophys., 1998, 29(1-2):113-32.
[6].  Lan Xiao, James P. O’Callaghan and James M. O’Donnell. Effects of Repeated Treatment with Phosphodiesterase-4 Inhibitors on cAMP Signaling, Hippocampal Cell Proliferation, and Behavior in the Forced-Swim Test. J. Pharmacol. Exp. Ther., 2011, 338(2):641-7.