基于哌嗪的CCR5拮抗剂作为HIV-1抑制剂。II. 1-[(2,4-二甲基-3-吡啶基)羰基]-4-甲基-4-[3(S)-甲基-4-[1(S)-[4-(三氟甲基)苯基]乙基]-1-哌嗪基]-哌啶N1-氧化物（Sch-350634）的发现，一种口服生物可利用的强效CCR5拮抗剂。
Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist.
作者信息
Tagat J R, Steensma R W, McCombie S W, Nazareno D V, Lin S I, Neustadt B R, Cox K, Xu S, Wojcik L, Murray M G, Vantuno N, Baroudy B M, Strizki J M
机构信息
Departments of Chemical Research, Drug Metabolism & Pharmacokinetics, and Antiviral Therapy, Schering-Plough Research Institute, K-15-2B-2800, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
出版信息
J Med Chem. 2001 Oct 11;44(21):3343-6. doi: 10.1021/jm0155401.
Truncation of the original piperidino-2(S)-methyl piperazine lead structure 2, from a family of muscarinic antagonists, gave compound 8 which has improved selectivity for the HIV-1 co-receptor CCR5 over muscarinic receptors. Further optimization for pharmacokinetic properties afforded Sch-350634 (1), a prototypical piperazine-based CCR5 antagonist, which is a potent inhibitor of HIV-1 entry and replication in PBMCs. The title compound (1) has excellent oral bioavailability in rat, dog, and monkey.
对毒蕈碱拮抗剂家族中的原始哌啶基-2(S)-甲基哌嗪先导结构2进行截短，得到了化合物8，该化合物对HIV-1共受体CCR5的选择性高于毒蕈碱受体。对药代动力学性质的进一步优化得到了Sch-350634（1），一种典型的基于哌嗪的CCR5拮抗剂，它是HIV-1进入和在PBMCs中复制的有效抑制剂。标题化合物（1）在大鼠、狗和猴子中具有优异的口服生物利用度。
Zotero 插件