TY - JOUR T1 - 3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1<em>H</em>-pyrazol-3-yl]-2-<em>m</em>-tolyl-propionate (JNJ-17156516), a Novel, Potent, and Selective Cholecystokinin 1 Receptor Antagonist: In Vitro and in Vivo Pharmacological Comparison with Dexloxiglumide JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 562 LP - 569 DO - 10.1124/jpet.107.124578 VL - 323 IS - 2 AU - Magda F. Morton AU - Terrance D. Barrett AU - Wen Yan AU - Jamie M. Freedman AU - Guy Lagaud AU - Clodagh E. Prendergast AU - Veronica Moreno AU - Jayashree Pyati AU - Katherine Figueroa AU - Lina Li AU - Xiaodong Wu AU - Michele Rizzolio AU - James G. Breitenbucher AU - Kelly McClure AU - Nigel P. Shankley Y1 - 2007/11/01 UR - http://jpet.aspetjournals.org/content/323/2/562.abstract N2 - 3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516) is a novel, potent, and selective cholecystokinin (CCK)1-receptor antagonist. In this study, the pharmacology of JNJ-17156516 was investigated both in vitro and in vivo, and the pharmacokinetic profile was evaluated in rats. JNJ-17156516 expressed high-affinity at the cloned human (pKI = 7.96 ± 0.11), rat (pKI = 8.02 ± 0.11), and canine (pKI = 7.98 ± 0.04) CCK1 receptors, and it was also highly selective for the CCK1 receptor compared with the CCK2 receptor across the same species (∼160-, ∼230-, and ∼75-fold, respectively). The high affinity of JNJ-17156516 at CCK1 receptors in vitro was confirmed in radioligand binding studies on fresh human gallbladder tissue (pKI = 8.22 ± 0.05). In a functional in vitro assay of guinea pig gallbladder contraction, JNJ-17156516 behaved as a competitive antagonist, with apKB value of 8.00 ± 0.07. In vivo, JNJ-17156516 produced a parallel, rightward shift in the CCK-8S-evoked contraction of the guinea pig gallbladder. The dose required to shift the CCK-8S dose-response curve was 240 nmol kg–1 i.v. In the anesthetized rat, JNJ-17156516 produced a dose-related decrease in the number of duodenal contractions evoked by infusion of CCK-8S, with an ED50 = 484 nmol kg–1. Pharmacokinetic analysis of JNJ-17156516 in rats, revealed that JNJ-17156516 had a half-life of 3.0 ± 0.5 h and a very high bioavailability (108 ± 10%) in this species. Overall, we have demonstrated that JNJ-17156516 is a high-affinity selective human CCK1 receptor antagonist with good pharmacokinetic properties in rats. The American Society for Pharmacology and Experimental Therapeutics ER -