Identification and Optimization of Anthranilic Sulfonamides as Novel, Selective Cholecystokinin-2 Receptor Antagonists
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- 作者：Brett D. Allison ; Victor K. Phuong ; Laura C. McAtee ; Mark Rosen ; Magda Morton ; Clodagh Prendergast ; Terry Barrett ; Guy Lagaud ; Jamie Freedman ; Lina Li ; Xiaodong Wu ; Hariharan Venkatesan ; Marna Pippel
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：October 19, 2006
- 年：2006
- 卷：49
- 期：21
- 页码：6371 - 6390
- 全文大小：325K
- 年卷期：v.49,no.21(October 19, 2006)
- ISSN：1520-4804
文摘
A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) 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, pKI = 6.4). Preliminaryexploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamidemoieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-foldselectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identificationof 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstratespromising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oralbioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat whendosed orally.