Exploiting the 2‑(1,3,4,9-tetrahydropyrano[3,4‑<i>b</i>]indol-1-yl)acetic Acid Scaffold to Generate COXTRANs: A New Class of Dual Cyclooxygenase Inhibitors-Thromboxane Receptor Antagonists

The use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs is effective for the treatment of inflammatory pain and chronic inflammatory conditions. However, their use is associated with enhanced risk of cardiovascular toxicity and thrombotic events, particularly for the latter. The vascular side effects of these drugs could be mitigated by pharmacological inhibition of the thromboxane A2 receptor (TP). Here we describe the development of a new class of dual cyclooxygenase (COX) inhibitors/thromboxane receptor antagonists (COXTRANs) based on the 2-(1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid scaffold. The in vitro evaluation of 50 newly synthesized compounds resulted in a set of well-balanced compounds exhibiting nanomolar activity on both COX-2 and TP receptor. Further studies in human whole blood and physicochemical profiling allowed the prioritization of 51 (CXT29) as a suitable candidate for in vivo studies. Compound 51, after oral administration, was able to prevent TP receptor-mediated platelet aggregation and to reduce inflammatory pain in mice.传统非甾体抗炎药（nonsteroidal anti-inflammatory drugs, NSAIDs）与昔布类（coxibs）药物在炎性疼痛及慢性炎症性疾病的治疗中疗效确切，但此类药物的使用会增加心血管毒性与血栓事件风险，尤以血栓事件为甚。研究表明，通过药理学手段抑制血栓烷A2受体（thromboxane A2 receptor, TP），可缓解这类药物引发的血管不良反应。本研究报道了一类基于2-(1,3,4,9-四氢吡喃并[3,4-b]吲哚-1-基)乙酸母核的新型双重环氧合酶（cyclooxygenase, COX）抑制剂/血栓烷受体拮抗剂（COXTRANs）的开发过程。对50个新合成化合物的体外评价结果显示，部分化合物对COX-2与TP受体均表现出纳摩尔级活性，且活性平衡良好。通过人全血实验与理化性质表征，最终优选出化合物51（CXT29）作为体内研究的候选化合物。化合物51经口服给药后，可阻断TP受体介导的血小板聚集，并减轻小鼠的炎性疼痛。