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4-[(Z)-(4-溴苯基)-(乙氧基亚氨基)甲基]-1'-[(2,4-二甲基-3-吡啶基)羰基]-4'-甲基-1,4'-联哌啶 N-氧化物（SCH 351125）的发现：一种口服生物可利用的人 CCR5 拮抗剂，用于治疗 HIV 感染。

Discovery of 4-[(Z)-(4-bromophenyl)- (ethoxyimino)methyl]-1'-[(2,4-dimethyl-3- pyridinyl)carbonyl]-4'-methyl-1,4'- bipiperidine N-oxide (SCH 351125): an orally bioavailable human CCR5 antagonist for the treatment of HIV infection.

作者信息

Palani A, Shapiro S, Clader J W, Greenlee W J, Cox K, Strizki J, Endres M, Baroudy B M

机构信息

Chemical Research, Drug Safety and Metabolism, and Antiviral Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.

出版信息

J Med Chem. 2001 Oct 11;44(21):3339-42. doi: 10.1021/jm015526o.

DOI:10.1021/jm015526o
PMID:11585437
Abstract

Structure-activity studies on piperidino-piperidine 3 led to the discovery of SCH 351125 (1), a selective CCR5 antagonist with potent activity against RANTES binding (K(i) = 2 nM), which possesses subnanomolar activity in blocking viral entry and has excellent antiviral potency versus a panel of primary HIV-1 viral isolates. Compound 1, which has good oral bioavailability in rats, dogs, and monkeys, is proposed as a potential therapeutic agent for the treatment of HIV-1 and has entered human clinical trials.

摘要

对哌啶基哌啶3进行的构效关系研究导致发现了SCH 351125（1），这是一种选择性CCR5拮抗剂，对RANTES结合具有强效活性（K(i)=2 nM），在阻断病毒进入方面具有亚纳摩尔活性，并且对一组原发性HIV-1病毒分离株具有优异的抗病毒效力。化合物1在大鼠、狗和猴子中具有良好的口服生物利用度，被提议作为治疗HIV-1的潜在治疗剂，并且已进入人体临床试验。

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1
Discovery of 4-[(Z)-(4-bromophenyl)- (ethoxyimino)methyl]-1'-[(2,4-dimethyl-3- pyridinyl)carbonyl]-4'-methyl-1,4'- bipiperidine N-oxide (SCH 351125): an orally bioavailable human CCR5 antagonist for the treatment of HIV infection.4-[(Z)-(4-溴苯基)-(乙氧基亚氨基)甲基]-1'-[(2,4-二甲基-3-吡啶基)羰基]-4'-甲基-1,4'-联哌啶 N-氧化物（SCH 351125）的发现：一种口服生物可利用的人 CCR5 拮抗剂，用于治疗 HIV 感染。
J Med Chem. 2001 Oct 11;44(21):3339-42. doi: 10.1021/jm015526o.
2
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.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。
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