Kaneko M, Saito Y, Saito H, Matsumoto T, Matsuda Y, Vaught J L, Dionne C A, Angeles T S, Glicksman M A, Neff N T, Rotella D P, Kauer J C, Mallamo J P, Hudkins R L, Murakata C
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
J Med Chem. 1997 Jun 6;40(12):1863-9. doi: 10.1021/jm970031d.
A series of 3,9 disubstituted [(alkylthio)methyl]- and (alkoxymethyl)-K-252a derivatives was synthesized with the aim of enhancing and separating the neurotrophic properties from the undesirable NGF (trk A kinase) and PKC inhibitory activities of K-252a. Data from this series reveal that substitution in the 3- and 9-positions of K-252a with these groups reduces trk A kinase inhibitory properties approximately 100- to > 500-fold while maintaining or in certain cases enhancing the neurotrophic activity. From this research, 3,9-bis[(ethylthio)methyl]-K-252a (8) was identified as a potent and selective neurotrophic agent in vitro as measured by enhancement of choline acetyltransferase activity in embryonic rat spinal cord and basal forebrain cultures. Compound 8 was found to have weak kinase inhibitory activity for trk A, protein kinase C1 protein kinase A, and myosin light chain kinase. On the basis of the in vitro profile, 8 was evaluated in in vivo models suggestive of neurological diseases. Compound 8 was active in preventing degeneration of cholinergic neurons of the nucleus basalis magnocellularis (NBM) and reduced developmentally programmed cell death (PCD) of female rat spinal nucleus of the bulbocavernosus motoneurons and embryonic chick lumbar motoneurons.
合成了一系列3,9-二取代的[(烷硫基)甲基]-和(烷氧基甲基)-K-252a衍生物，目的是增强并区分K-252a的神经营养特性与不良的NGF（trk A激酶）和PKC抑制活性。该系列的数据表明，在K-252a的3位和9位用这些基团进行取代可使trk A激酶抑制特性降低约100至>500倍，同时保持或在某些情况下增强神经营养活性。通过在胚胎大鼠脊髓和基底前脑培养物中增强胆碱乙酰转移酶活性来衡量，从该研究中确定3,9-双[(乙硫基)甲基]-K-252a（8）在体外是一种有效的选择性神经营养剂。发现化合物8对trk A、蛋白激酶C1、蛋白激酶A和肌球蛋白轻链激酶具有较弱的激酶抑制活性。基于体外特性，在提示神经系统疾病的体内模型中对8进行了评估。化合物8在预防大细胞基底核（NBM）胆碱能神经元变性以及减少雌性大鼠球海绵体运动神经元脊髓核和胚胎鸡腰运动神经元发育程序性细胞死亡（PCD）方面具有活性。
