Fish Paul V, Wakenhut Florian, Ryckmans Thomas, Stobie Alan
Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK.
Bioorg Med Chem Lett. 2009 Aug 15;19(16):4579-83. doi: 10.1016/j.bmcl.2009.06.096. Epub 2009 Jul 2.
Derivatives of N-[(3S)-pyrrolidin-3-yl]benzamides are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Structure-activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenyl ring; consequently, selective NRIs and dual NSRIs were prepared. Benzamide 11e was identified as a potent NRI with good selectivity over SRI and DRI, good in vitro metabolic stability, weak CYP inhibition and low affinity for ion channels. Evaluation in vivo, in rat microdialysis experiments, showed 11e increased noradrenaline levels by up to 350% confirming good CNS penetration. Benzamide 11e was differentiated from previous NRIs as it was significantly less lipophilic (DeltaclogP -0.9).
N-[(3S)-吡咯烷-3-基]苯甲酰胺的衍生物被披露为一类新型的去甲肾上腺素再摄取抑制剂（NRI）。构效关系表明，通过在苯环的2-位进行适当取代可实现强效的NRI活性；因此，制备了选择性NRI和双重NSRI。苯甲酰胺11e被鉴定为一种强效NRI，对SRI和DRI具有良好的选择性，体外代谢稳定性良好，对CYP的抑制作用较弱，对离子通道的亲和力较低。在大鼠微透析实验中的体内评估表明，11e可使去甲肾上腺素水平升高高达350%，证实其具有良好的中枢神经系统渗透性。苯甲酰胺11e与先前的NRI不同，因为它的亲脂性显著较低（ΔcLogP -0.9）。
