Piperazine-based CCR5 antagonists as HIV-1 inhibitors.: IV.: Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-{2-methoxy-1(R)-4-(trifluoromethyl)-phenyl}ethyl-3(S)-methyl-1-piperazinyl]-4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist

被引：134

作者：

Tagat, JR ^{[1
]}

McCombie, SW ^{[1
]}

Nazareno, D ^{[1
]}

Labroli, MA ^{[1
]}

Xiao, YS ^{[1
]}

Steensma, RW ^{[1
]}

Strizki, JM ^{[1
]}

Baroudy, BM ^{[1
]}

Cox, K ^{[1
]}

Lachowicz, J ^{[1
]}

Varty, G ^{[1
]}

Watkins, R ^{[1
]}

机构：

[1] Schering Plough Res Inst, Kenilworth, NJ 07033 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 10期

关键词：

D O I：

10.1021/jm0304515

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.

引用

页码：2405 / 2408

页数：4

共 16 条

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