Elliott R L, Kopecka H, Bennett M J, Shue Y K, Craig R, Lin C W, Bianchi B R, Miller T R, Witte D G, Stashko M A
Department 47W, Abbott Laboratories, Abbott Park, Illinois 60064.
J Med Chem. 1994 Jan 21;37(2):309-13. doi: 10.1021/jm00028a015.
We had reported earlier on a novel series of potent and selective tetrapeptide cholecystokinin-A (CCK-A) agonists of the general structure Boc-Trp-Lys[epsilon-Y]-Asp-N(R)PheNH2 [Y = amides, ureas; R = H, Me] that were potent anorectic agents in rats. In an effort to optimize the potency, selectivity, stability, and efficacy of our lead candidate A-71623 [R = Me, Y = o-tolylaminocarbonyl; Tac] toward development of a clinical candidate, we have explored a series of analogues in which the N-terminal Boc functionality was systematically replaced with various amides, ureas, carbamates, and sulfonamides of differing size, hydrophobicity, and stereoelectronic properties. In general, these analogues maintained good potency and selectivity for the CCK-A receptor (guinea pig pancreas), as well as potent anorectic activity in rats. Those analogues exhibiting equal or superior activity compared to A-71623 but differing physicochemical properties may represent superior drug candidates.
我们之前报道过一系列新型的、高效且具选择性的四肽胆囊收缩素A（CCK-A）激动剂，其通式为Boc-Trp-Lys[ε-Y]-Asp-N(R)PheNH2 [Y = 酰胺、脲；R = H、Me]，这些激动剂在大鼠中是强效的食欲抑制剂。为了优化我们的先导候选物A-71623 [R = Me，Y = 邻甲苯氨基羰基；Tac] 的效力、选择性、稳定性和功效，以开发临床候选药物，我们探索了一系列类似物，其中N端的Boc官能团被具有不同大小、疏水性和立体电子性质的各种酰胺、脲、氨基甲酸酯和磺酰胺系统地取代。总体而言，这些类似物对CCK-A受体（豚鼠胰腺）保持了良好的效力和选择性，以及在大鼠中的强效食欲抑制活性。那些与A-71623相比表现出同等或更高活性但物理化学性质不同的类似物可能代表着更优的候选药物。
