Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy
Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy
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DOI：
10.1124/mol.115.101832
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发表时间：
2016-05-01
影响因子：
3.6
通讯作者：
Charlton, Steven J.
中科院分区：
文献类型：
--
作者：
Sykes, David A.;Bradley, Michelle E.;Charlton, Steven J.
在这里，我们描述了一系列临床相关的趋化因子受体同源分子表达的辅助性T细胞2型（CRTh 2）受体拮抗剂，包括非匹普兰（NVP-QAW 039或QAW 039），这是目前正在开发的治疗过敏性疾病的药理学特性。[H-3]-QAW 039对中国仓鼠卵巢细胞中表达的人CRTh 2受体显示出高亲和力（1.14 +/- 6 0.44 nM），结合可逆，并与天然激动剂前列腺素D-2（PGD（2））竞争。使用[H-3]-QAW 039直接测定的QAW 039结合动力学显示，QAW 039的平均动力学开（k（on））和关（k（off））值分别为4.5 x 10（7）M-1 min（-1）和0.048 min（-1）。重要的是，QAW 039的k（off）（半衰期= 14.4分钟）比测试的最慢的参比化合物AZD-1981慢>7倍。在功能研究中，QAW 039表现为PGD（2）刺激的[S-35]-GTP γ S激活的难以克服的拮抗剂，并且在初始15分钟孵育期后，其作用不能通过增加PGD 2浓度完全逆转。这种行为与其与人CRTh 2受体相对缓慢的解离一致。相反，对于测试的其他配体，这种对最大刺激的时间依赖性作用在15分钟时间点完全逆转，而QAW 039的作用持续了。180分钟。测试的所有CRTh 2拮抗剂都抑制PGD（2）刺激的人嗜酸性粒细胞形状变化，但重要的是，相对于分离的形状变化测定，QAW 039在全血形状变化测定中保留了其效力，这可能反映了其相对较慢的CRTh 2受体解离速率。QAW 039也是人Th 2细胞中PGD（2）诱导的细胞因子释放的有效抑制剂。CRTh 2拮抗剂的缓慢解离可以在病理性PGD（2）浓度下增加受体覆盖，这可能与临床相关。
Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [H-3]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 +/- 6 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D-2 (PGD(2)). The binding kinetics of QAW039 determined directly using [H-3]-QAW039 revealed mean kinetic on (k(on)) and off (k(off)) values for QAW039 of 4.5 x 10(7) M-1 min(-1) and 0.048 minute(-1), respectively. Importantly, the k(off) of QAW039 (half-life = 14.4 minutes) was >7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD(2)-stimulated [S-35]-GTP gamma S activation, and its effects were not fully reversed by increasing concentrations of PGD2 after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for. 180 minutes. All CRTh2 antagonists tested inhibited PGD(2)-stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD(2)-induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD(2) concentrations, which may be clinically relevant.