A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.

中文翻译：

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发现MK-8318，一种有效的选择性CRTh2受体拮抗剂，用于治疗哮喘

一系列新的三环四氢喹啉被鉴定为有效的和选择性的CRTh2受体拮抗剂。通过使用CRTh2受体同源模型的基于结构的药物设计（SBDD）实现了激动和拮抗作用的转换。通过针对三环核心的SAR研究，通过详尽的药物化学铅优化，克服了药代动力学研究中极低暴露的挑战。进一步的优化导致临床前候选药物4-（环丙基（（3 aS，9 R，9 aR）-7-氟-4-（4-（三氟甲氧基）苯甲酰基）-2,3,3 a，4， 9,9-一个-六氢- 1 H ^环戊二烯并[ b ]喹啉-9-基）氨基）-4-氧代丁酸（15c，MK-8318）具有有效的和选择性的CRTh2拮抗剂活性和有利的PK曲线，适于每天一次口服给药以潜在地治疗哮喘。