Spirodiketopiperazine-based CCR5 antagonist: Discovery of an antiretroviral drug candidate

被引：9

作者：

Nishizawa, Rena ^{[1
]}

Nishiyama, Toshihiko ^{[1
]}

Hisaichi, Katsuya ^{[1
]}

Minamoto, Chiaki ^{[1
]}

Matsunaga, Naoki ^{[1
]}

Takaoka, Yoshikazu ^{[1
]}

Nakai, Hisao ^{[1
]}

Jenkinson, Stephen ^{[3
]}

Kazmierski, Wieslaw M. ^{[3
]}

Tada, Hideaki ^{[2
]}

Sagawa, Kenji ^{[2
]}

Shibayama, Shiro ^{[2
]}

Fukushima, Daikichi ^{[2
]}

Maeda, Kenji ^{[4
,5
]}

Mitsuya, Hiroaki ^{[4
,5
]}

机构：

[1] Ono Pharmaceut Co Ltd, Med Chem Res Lab, Osaka 6188585, Japan

[2] Ono Pharmaceut Co Ltd, Exploratory Res Lab, Ibaraki 300424, Japan

[3] GlaxoSmithKline Res & Dev Ltd, Res Triangle Pk, NC 27709 USA

[4] Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8600811, Japan

[5] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 04期

关键词：

CCR5; Chemokine; Anti-HIV; CHEMOKINE RECEPTOR; HIV-1; INFECTION; VIRAL ENTRY; CORECEPTOR; COFACTOR; POTENT;

D O I：

10.1016/j.bmcl.2010.12.109

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate. (c) 2010 Elsevier Ltd. All rights reserved.

引用

页码：1141 / 1145

页数：5

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