Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one-based novel chemotype CCR2 antagonists via scaffold hopping strategy
Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one-based novel chemotype CCR2 antagonists via scaffold hopping strategy
复制标题
通过支架跳跃策略发现和合成基于 6,7,8,9-四氢-5H-pyrido[4,3-c]azepin-5-one 的新型化学型 CCR2 拮抗剂
DOI：
10.1016/j.bmc.2018.05.027
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发表时间：
2018
影响因子：
3.5
通讯作者：
Long Ya-Qiu
中科院分区：
文献类型：
--
作者：
Qin Li-Huai;Wang Zhi-Long;Xie Xin;Long Ya-Qiu
趋化因子CC受体亚型2(CCR2)在慢性炎症性疾病、糖尿病、神经病理性疼痛、动脉粥样硬化和癌症等多种治疗领域的药物开发中引起了广泛的兴趣。通过采用切割缝合支架跳跃策略，我们确定了3，4-二氢-2，6-萘啶-1(2H)-酮的活性支架作为中心药效团来衍生新的CCR2拮抗剂。系统的构效关系研究表明，1-arylamino-6-alkylheterocycle-6，7，8，9-tetrahydro-5H-pyrido[4，3-c]azepin-5-ones是一种新型的具有纳米分子抑制活性的CCR2拮抗剂。化合物13a的拮抗活性最好，它结合了C-1位的3，4-二氯苯氨基和N-6位的3-(4-(N-methylmethylsulfonamido)piperidin-1-yl)propyl的最佳取代反应，其IC50值为61 NM，选择性是CCR5的10倍。为了构建创新的核心结构和衍生化合物集合，建立了高效和通用的合成方法。这是首次报道我们设计的新型CCR2拮抗剂支架6，7，8，9-tetrahydro-5H-pyrido[4，3-c]azepin-5-one及其合成。
The chemokine CC receptor subtype 2 (CCR2) has attracted intensive interest for drug development in diverse therapeutic areas, including chronic inflammatory diseases, diabetes, neuropathic pain, atherogenesis and cancer. By employing a cut-and-sew scaffold hopping strategy, we identified an active scaffold of 3,4-dihydro-2,6-naphthyridin-1(2H)-one as the central pharmacophore to derive novel CCR2 antagonists. Systematic structure–activity relationship study with respect to the ring size and the substitution on the naphthyridinone ring gave birth to 1-arylamino-6-alkylheterocycle-6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-ones as a brand new chemotype of CCR2 antagonists with nanomolar inhibitory activity. The best antagonism activity in this series was exemplified by compound13a, which combined the optimal substitutions of 3,4-dichlorophenylamino at C-1 and 3-(4-(N-methylmethylsulfonamido)piperidin-1-yl)propyl at N-6 position, leading to an IC50value of 61 nM and 10-fold selectivity for CCR2 over CCR5. Efficient and general synthesis was established to construct the innovative core structure and derive the compound collections. This is the first report on our designed 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one as novel CCR2 antagonist scaffold and its synthesis.