Metabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitution

被引：14

作者：

Boyle, CD ^{[1
]}

Chackalamannil, S ^{[1
]}

Clader, JW ^{[1
]}

Greenlee, WJ ^{[1
]}

Josien, HB ^{[1
]}

Kaminski, JJ ^{[1
]}

Kozlowski, JA ^{[1
]}

McCombie, SW ^{[1
]}

Nazareno, DV ^{[1
]}

Tagat, JR ^{[1
]}

Wang, YG ^{[1
]}

Zhou, GW ^{[1
]}

Billard, W ^{[1
]}

Binch, H ^{[1
]}

Crosby, G ^{[1
]}

Cohen-Williams, M ^{[1
]}

Coffin, VL ^{[1
]}

Cox, KA ^{[1
]}

Grotz, DE ^{[1
]}

Duffy, RA ^{[1
]}

Ruperto, V ^{[1
]}

Lachowicz, JE ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2001年 / 11卷 / 17期

关键词：

D O I：

10.1016/S0960-894X(01)00435-8

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The potential toxicological liabilities of the M-2 muscarinic antagonist I were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M-2 selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M2 affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates. (C) 2001 Elsevier Science Ltd. All rights reserved.

引用

页码：2311 / 2314

页数：4

共 26 条

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