Castro J L, Broughton H B, Russell M G, Rathbone D, Watt A P, Ball R G, Chapman K L, Patel S, Smith A J, Marshall G R, Matassa V G
Chemistry Department, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, U.K.
J Med Chem. 1997 Aug 1;40(16):2491-501. doi: 10.1021/jm9608523.
The design, synthesis, and biological activity of a series of high-affinity, basic ligands for the cholecystokinin-B receptor are described. The compounds, which incorporate a piperidin-2-yl or a homopiperidin-2-yl group attached to C5 of a benzodiazepine core structure, are substantially more basic (e.g., 9d, pKa = 9.48) than previously reported antagonists based on 5-amino-1,4-benzodiazepines (e.g., 5, pKa = 7.1) and have improved aqueous solubility. In view of their basicity, it would be tempting to speculate that the present series of compounds might be binding to the CCK-B receptor in their protonated form. Compounds such as 9d, e and 10d showed high affinity for this receptor (IC50 < 2.5 nM) and very good selectivity over CCK-A (CCK-A/CCK-B > 2000), even as the racemates. Additionally, a significantly improved in vivo half-life was observed for a selection of compounds compared to the clinical candidate L-365, -260 (1).
描述了一系列对胆囊收缩素B受体具有高亲和力的碱性配体的设计、合成及生物活性。这些化合物在苯二氮䓬核心结构的C5位连接有哌啶-2-基或高哌啶-2-基，其碱性（如9d，pKa = 9.48）比先前报道的基于5-氨基-1,4-苯二氮䓬的拮抗剂（如5，pKa = 7.1）强得多，且水溶性有所改善。鉴于它们的碱性，很容易推测本系列化合物可能以质子化形式与CCK-B受体结合。化合物9d、e和10d等对该受体表现出高亲和力（IC50 < 2.5 nM），并且即使作为外消旋体，对CCK-A的选择性也非常好（CCK-A/CCK-B > 2000）。此外，与临床候选药物L-365, -260（1）相比，部分化合物的体内半衰期有显著提高。
