Imamura Shinichi, Ichikawa Takashi, Nishikawa Youichi, Kanzaki Naoyuki, Takashima Katsunori, Niwa Shinichi, Iizawa Yuji, Baba Masanori, Sugihara Yoshihiro
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka 532-8686, Japan.
J Med Chem. 2006 May 4;49(9):2784-93. doi: 10.1021/jm051034q.
We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC(50) = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-[4-(4-carbamoylbenzyl)piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC(50) = 3.5 nM) and potent inhibition of membrane fusion (IC(50) = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC(50) = 1.1 nM, EC(90) = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.
我们将各种极性基团引入先前描述的哌啶 - 4 - 甲酰胺CCR5拮抗剂中，以提高它们在人肝微粒体中的代谢稳定性。在4 - 苄基哌啶部分的苯环中引入氨基甲酰基得到了亲脂性较低的化合物5f，其具有高代谢稳定性和对HIV - 1包膜介导的膜融合的良好抑制活性（IC(50)=5.8 nM）。为了提高效力进行的进一步优化导致发现了1 - 乙酰基 - N - {3 - [4 - (4 - 氨基甲酰基苄基)哌啶 - 1 - 基]丙基}-N - (3 - 氯 - 4 - 甲基苯基)哌啶 - 4 - 甲酰胺（5m，TAK - 220），其显示出高CCR5结合亲和力（IC(50)=3.5 nM）和对膜融合的有效抑制（IC(50)=0.42 nM），以及良好的代谢稳定性。化合物5m强烈抑制使用CCR5的HIV - 1临床分离株在人外周血单核细胞中的复制（平均EC(50)=1.1 nM，EC(90)=13 nM），并且在猴子中表现出良好的药代动力学特征（BA = 29％）。该化合物已被选为进一步开发的临床候选药物。
