Laufer Stefan A, Margutti Simona, Fritz Martina D
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
ChemMedChem. 2006 Feb;1(2):197-207. doi: 10.1002/cmdc.200500025.
In a continuous effort to develop improved p38 MAP (mitogen-activated protein) kinase inhibitors, we focused our attention on the suitability of the isoxazole ring as a bioisosteric replacement for the imidazole ring of SB-203580. 3,4- and 4,5-disubstituted as well as 3,4,5-trisubstituted isoxazole derivatives were synthesized. These compounds were tested in an in vitro enzyme-linked immunosorbent assay of isolated p38 MAP kinase and for inhibitory potency against cytochrome P450. Compound 4 a displays a highly promising profile for development as an anti-inflammatory agent owing to its enhanced suppression of cytokine release, decreased affinity for cytochrome P450 and a twofold decrease in IC50 toward isolated p38 MAP kinase.
为持续研发更优的p38丝裂原活化蛋白（MAP）激酶抑制剂，我们将注意力集中在异恶唑环作为SB - 203580咪唑环生物电子等排体替代物的适用性上。合成了3,4 - 二取代、4,5 - 二取代以及3,4,5 - 三取代的异恶唑衍生物。这些化合物在分离的p38 MAP激酶的体外酶联免疫吸附测定中进行了测试，并检测了其对细胞色素P450的抑制效力。化合物4a因其对细胞因子释放的抑制增强、对细胞色素P450的亲和力降低以及对分离的p38 MAP激酶的IC50降低两倍，显示出作为抗炎剂开发的极具前景的特性。
