Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2

被引：3

作者：

Yang, Michael G. ^{[1
]}

Xiao, Zili ^{[1
]}

Zhao, Rulin ^{[1
]}

Tebben, Andrew J. ^{[1
]}

Wang, Bei ^{[1
]}

Cherney, Robert J. ^{[1
]}

Batt, Douglas G. ^{[1
]}

Brown, Gregory D. ^{[1
]}

Cvijic, Mary Ellen ^{[1
]}

Duncia, John, V ^{[1
]}

Gallela, Michael A. ^{[1
]}

Gardner, Daniel S. ^{[1
]}

Khandelwal, Purnima ^{[1
]}

Malley, Mary F. ^{[1
]}

Pang, Jian ^{[1
]}

Rose, Anne, V ^{[1
]}

Santella, Joseph B., III ^{[1
]}

Sarjeant, Amy A. ^{[1
]}

Xu, Songmei ^{[1
]}

Mathur, Arvind ^{[1
]}

Mandlekar, Sandhya ^{[1
]}

Vuppugalla, Ragini ^{[1
]}

Zhao, Qihong ^{[1
]}

Carter, Percy H. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Res & Dev, Princeton, NJ 08543 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2021年 / 12卷 / 06期

关键词：

CC chemokine receptor 2 (CCR2); CCR2; antagonist; Monocyte chemoattractant protein-1; Multiple sclerosis; TARGETS; BIOLOGY;

D O I：

10.1021/acsmedchemlett.1c00082

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate la, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCRS and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.

引用

页码：969 / 975

页数：7

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Taub, D
Dunning, L
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Snider, RM
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