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发现和优化联芳基烷基醚作为一类新型高选择性、可穿透 CNS 和口服活性衔接蛋白 2 相关激酶 1 (AAK1) 抑制剂，用于潜在治疗神经性疼痛
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-03-09 , DOI: 10.1021/acs.jmedchem.1c02132 Guanglin Luo 1 , Ling Chen 1 , Walter A Kostich 2 , Brian Hamman 3 , Jason Allen 3 , Amy Easton 2 , Clotilde Bourin 2 , Michael Gulianello 2 , Jonathan Lippy 4 , Susheel Nara 5 , Sreenivasulu Naidu Pattipati 5 , Kumaran Dandapani 5 , Manoj Dokania 5 , Pradeep Vattikundala 5 , Vivek Sharma 5 , Saravanan Elavazhagan 5 , Manoj Kumar Verma 5 , Manish Lal Das 5 , Santosh Wagh 5 , Anand Balakrishnan 6 , Benjamin M Johnson 6 , Kenneth S Santone 6 , George Thalody 7 , Rex Denton 7 , Hariharan Saminathan 5 , Vinay K Holenarsipur 5 , Anoop Kumar 5 , Abhijith Rao 5 , Siva Prasad Putlur 5 , Sarat Kumar Sarvasiddhi 5 , Ganesh Shankar 5 , Justin V Louis 5 , Manjunath Ramarao 5 , Charles M Conway 2 , Yu-Wen Li 2 , Rick Pieschl 2 , Yuan Tian 2 , Yang Hong 2 , Linda Bristow 2 , Charles F Albright 2 , Joanne J Bronson 1 , John E Macor 1 , Carolyn D Dzierba 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-03-09 , DOI: 10.1021/acs.jmedchem.1c02132 Guanglin Luo 1 , Ling Chen 1 , Walter A Kostich 2 , Brian Hamman 3 , Jason Allen 3 , Amy Easton 2 , Clotilde Bourin 2 , Michael Gulianello 2 , Jonathan Lippy 4 , Susheel Nara 5 , Sreenivasulu Naidu Pattipati 5 , Kumaran Dandapani 5 , Manoj Dokania 5 , Pradeep Vattikundala 5 , Vivek Sharma 5 , Saravanan Elavazhagan 5 , Manoj Kumar Verma 5 , Manish Lal Das 5 , Santosh Wagh 5 , Anand Balakrishnan 6 , Benjamin M Johnson 6 , Kenneth S Santone 6 , George Thalody 7 , Rex Denton 7 , Hariharan Saminathan 5 , Vinay K Holenarsipur 5 , Anoop Kumar 5 , Abhijith Rao 5 , Siva Prasad Putlur 5 , Sarat Kumar Sarvasiddhi 5 , Ganesh Shankar 5 , Justin V Louis 5 , Manjunath Ramarao 5 , Charles M Conway 2 , Yu-Wen Li 2 , Rick Pieschl 2 , Yuan Tian 2 , Yang Hong 2 , Linda Bristow 2 , Charles F Albright 2 , Joanne J Bronson 1 , John E Macor 1 , Carolyn D Dzierba 1
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最近的小鼠基因敲除研究将接头蛋白 2 相关激酶 1 (AAK1) 确定为治疗神经性疼痛的可行靶标。BMS-986176/LX-9211 ( 4 ) 作为一种高选择性、可穿透 CNS 且有效的 AAK1 抑制剂，已进入 II 期人体试验。在探索这种联芳基烷基醚化学型的构效关系 (SAR) 时，发现几种其他化合物是具有良好药物样特性的高选择性和强效 AAK1 抑制剂。其中，化合物43和58在两种神经性疼痛大鼠模型中显示出非常好的疗效，并具有出色的中枢神经系统穿透和脊髓靶点接合。这两种化合物还表现出良好的物理化学和口服药代动力学 (PK) 特性。化合物58是 BMS-986176/LX-9211 ( 4 ) 的中心吡啶异构体，在体外比4的效力高 4倍，并且与 CCI 大鼠模型中的4相比，显示出实现相似功效所需的较低血浆暴露。然而，与4相比， 43和58的临床前毒性特征均较差。
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更新日期：2022-03-09
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