Imamura Shinichi, Kurasawa Osamu, Nara Yoshi, Ichikawa Takashi, Nishikawa Youichi, Iida Takehiro, Hashiguchi Shohei, Kanzaki Naoyuki, Iizawa Yuji, Baba Masanori, Sugihara Yoshihiro
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
Bioorg Med Chem. 2004 May 1;12(9):2295-306. doi: 10.1016/j.bmc.2004.02.004.
We have previously reported the novel lead compound 1a as a CCR5 antagonist for treatment of HIV-1 infection. SAR studies on incorporating various acyl groups as a replacement for the 5-oxopyrrolidine-3-carbonyl group of the lead structure resulted in the discovery of N-[3-(4-benzylpiperidin-1-yl)propyl]-N,N'-diphenylurea (4a) with significantly improved CCR5 binding affinity. Substitutions (4-Cl, 4e,f; 4-Me, 4i) on the N'-phenyl ring further increased the binding affinity. Introduction of polar substituents on the phenyl ring of the 4-benzylpiperidine moiety enhanced the inhibitory activity of the HIV-1 envelope-mediated membrane fusion (4v,w), suggesting that polar substituents at this position can interfere effectively with HIV-1 cell entry.
我们之前已报道新型先导化合物1a作为一种CCR5拮抗剂用于治疗HIV-1感染。对引入各种酰基以取代先导结构的5-氧代吡咯烷-3-羰基进行的构效关系研究，导致发现了N-[3-(4-苄基哌啶-1-基)丙基]-N,N'-二苯基脲(4a)，其CCR5结合亲和力显著提高。在N'-苯环上进行取代(4-氯，4e,f；4-甲基，4i)进一步提高了结合亲和力。在4-苄基哌啶部分的苯环上引入极性取代基增强了HIV-1包膜介导的膜融合的抑制活性(4v,w)，这表明该位置的极性取代基可有效干扰HIV-1进入细胞。
