Identification and optimization of anthranilic sulfonamides as novel, selective cholecystokinin-2 receptor antagonists

被引：35

作者：

Allison, Brett D. ^{[1
]}

Phuong, Victor K. ^{[1
]}

McAtee, Laura C. ^{[1
]}

Rosen, Mark ^{[1
]}

Morton, Magda ^{[1
]}

Prendergast, Clodagh ^{[1
]}

Barrett, Terry ^{[1
]}

Lagaud, Guy ^{[1
]}

Freedman, Jamie ^{[1
]}

Li, na Li ^{[1
]}

Wu, Xiaodong ^{[1
]}

Venkatesan, Hariharan ^{[1
]}

Pippel, Marna ^{[1
]}

Woods, Craig ^{[1
]}

Rizzolio, Michele C. ^{[1
]}

Hack, Michael ^{[1
]}

Hoey, Kenway ^{[1
]}

Deng, Xiaohu ^{[1
]}

King, Christopher ^{[1
]}

Shankley, Nigel P. ^{[1
]}

Rabinowitz, Michael H. ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 21期

关键词：

D O I：

10.1021/jm060590x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]- piperidine (1;CCK-2R, pK(I)) 6.4). Preliminary exploration of the structure- activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl) amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.

引用

页码：6371 / 6390

页数：20

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