Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Science , VU University Amsterdam , De Boelelaan 1083 , 1081 HV Amsterdam , The Netherlands.
Operations, BioPharmaceuticals R&D , AstraZeneca , Alderley Park , Macclesfield SK10 4TG , United Kingdom.
J Med Chem. 2019 Jul 25;62(14):6630-6644. doi: 10.1021/acs.jmedchem.9b00447. Epub 2019 Jul 5.
Drug-target binding kinetics are an important predictor of in vivo drug efficacy, yet the relationship between ligand structures and their binding kinetics is often poorly understood. We show that both rupatadine () and desloratadine () have a long residence time at the histamine H receptor (HR). Through development of a [H]levocetirizine radiolabel, we find that the residence time of exceeds that of more than 10-fold. This was further explored with 22 synthesized rupatadine and desloratadine analogues. Methylene-linked cycloaliphatic or β-branched substitutions of desloratadine increase the residence time at the HR, conveying a longer duration of receptor antagonism. However, cycloaliphatic substituents directly attached to the piperidine amine (i.e., lacking the spacer) have decreased binding affinity and residence time compared to their methylene-linked structural analogues. Guided by docking studies, steric constraints within the binding pocket are hypothesized to explain the observed differences in affinity and binding kinetics between analogues.
药物-靶标结合动力学是体内药物疗效的一个重要预测指标，但配体结构与其结合动力学之间的关系往往知之甚少。我们表明，芦氯他定（）和地氯雷他定（）在组胺 H 受体（HR）上都具有较长的停留时间。通过开发[H]左西替利嗪放射性标记物，我们发现的停留时间超过了的停留时间 10 倍以上。这通过 22 种合成的芦氯他定和地氯雷他定类似物进一步进行了探索。地氯雷他定中环脂族亚甲基连接或 β-支链取代增加了在 HR 上的停留时间，从而延长了受体拮抗作用的持续时间。然而，与亚甲基连接的结构类似物相比，直接连接到哌啶胺的脂环取代基（即没有间隔物）的结合亲和力和停留时间降低。受对接研究的指导，假设结合口袋内的空间位阻可以解释类似物之间亲和力和结合动力学观察到的差异。
