Lee Ki Yong, Lee Kwang Seob, Jin Changbae, Lee Yong Sup
Kyung Hee East-West Pharmaceutical Research Institute, Department of Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
Eur J Med Chem. 2009 Mar;44(3):1331-4. doi: 10.1016/j.ejmech.2008.02.023. Epub 2008 Mar 7.
Excessive calpain activation contributes to serious cellular damage in many pathological conditions. The involvement of mu-calpain in neurological disorders such as, stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 6-Pyridone 2-carboxamides derived from ketoamides were synthesized as conformationally constrained structures resembling the well known peptidic mu-calpain inhibitor, MDL 28,170, and their mu-calpain inhibitory activities were evaluated. Of the compounds synthesized, compound 2a, which has a primary amide at warhead region of the inhibitor most potently inhibited mu-calpain with an IC(50) value of 2.81+/-1.26 microM, which is ca. 40-fold less than that of MDL 28,170.
在许多病理状况下，钙蛋白酶的过度激活会导致严重的细胞损伤。μ-钙蛋白酶参与诸如中风和阿尔茨海默病等神经疾病，这使得人们对使用钙蛋白酶抑制剂作为治疗药物产生了浓厚兴趣。合成了源自酮酰胺的6-吡啶酮-2-羧酰胺，其为构象受限结构，类似于著名的肽类μ-钙蛋白酶抑制剂MDL 28,170，并对它们的μ-钙蛋白酶抑制活性进行了评估。在所合成的化合物中，在抑制剂弹头区域含有伯酰胺的化合物2a最有效地抑制了μ-钙蛋白酶，其IC(50)值为2.81±1.26 μM，约为MDL 28,170的1/40。
