Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: Assessment of potency, efficacy, and cardiovascular safety

被引：49

作者：

Lynch, John K. ^{[1
]}

Freeman, Jennifer C. ^{[1
]}

Judd, Andrew S. ^{[1
]}

Iyengar, Rajesh ^{[1
]}

Mulhern, Mathew ^{[1
]}

Zhao, Gang ^{[1
]}

Napier, James J. ^{[1
]}

Wodka, Dariusz ^{[1
]}

Brodjian, Sevan ^{[1
]}

Dayton, Brian D. ^{[1
]}

Falls, Doug ^{[1
]}

Ogiela, Christopher ^{[1
]}

Reilly, Regina M. ^{[1
]}

Campbell, Thomas J. ^{[1
]}

Polakowski, James S. ^{[1
]}

Hernandez, Lisa ^{[1
]}

Marsh, Kennan C. ^{[1
]}

Shapiro, Robin ^{[1
]}

Knourek-Segel, Victoria ^{[1
]}

Droz, Brian ^{[1
]}

Bush, Eugene ^{[1
]}

Brune, Michael ^{[1
]}

Preusser, Lee C. ^{[1
]}

Fryer, Ryan M. ^{[1
]}

Reinhart, Glenn A. ^{[1
]}

Houseman, Kathryn ^{[1
]}

Diaz, Gilbert ^{[1
]}

Mikhail, Ann ^{[1
]}

Limberis, James T. ^{[1
]}

Sham, Hing L. ^{[1
]}

Collins, Christine A. ^{[1
]}

Kym, Philip R. ^{[1
]}

机构：

[1] Abbott Labs, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 22期

关键词：

D O I：

10.1021/jm060683e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.

引用

页码：6569 / 6584

页数：16

共 25 条

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