Brett D Allison,
Victor K Phuong,
Laura C McAtee,
Mark Rosen,
Magda Morton,
Clodagh Prendergast, Terry Barrett,
Guy Lagaud,
Jamie Freedman,
Lina Li, [......],
Hariharan Venkatesan,
Marna Pippel,
Craig Woods,
Michèle C Rizzolio,
Michael Hack,
Kenway Hoey,
Xiaohu Deng,
Christopher King,
Nigel P Shankley,
Michael H Rabinowitz
[show abstract]
[hide abstract]
ABSTRACT: 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, 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.
Journal of Medicinal Chemistry 11/2006; 49(21):6371-90. · 5.25 Impact Factor
