Structure-based led optimisation of orally active reversible Methionine Aminopeptidase-2 (MetAP-2) inhibitors utilising a ‘molecular budget’ medicinal chemistry strategy is described. The key physicochemical parameters of target molecules (cLogP, molecular size and H-bond donor count) were monitored through straightforward and intuitive use of atom count and distribution. The balance between structure-based design and an awareness of the physico-chemical properties of the compounds synthesised enabled the rapid identification of a potent molecule with good oral pharmacokinetic (PK) characteristics by making fewer, higher quality compounds. The resulting candidate quality molecule was validated in a mechanistic cellular assay and a rodent secondary immunisation model.

描述了利用“分子预算”药物化学策略对口服活性可逆蛋氨酸氨基肽酶-2（MetAP-2）抑制剂进行基于结构的优化。通过直接和直观地使用原子计数和分布，可以监控目标分子的关键物理化学参数（cLogP，分子大小和H键供体计数）。在基于结构的设计与对合成化合物的理化性质的了解之间的平衡，使得能够通过生产更少，质量更高的化合物来快速鉴定具有良好口服药代动力学（PK）特征的有效分子。在机械细胞分析和啮齿动物第二次免疫模型中验证了所得候选质量分子。