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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 7, 2007; DOI: 10.1124/jpet.107.124578

0022-3565/07/3232-562-569$20.00
JPET 323:562-569, 2007
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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516), a Novel, Potent, and Selective Cholecystokinin 1 Receptor Antagonist: In Vitro and in Vivo Pharmacological Comparison with Dexloxiglumide

Magda F. Morton, Terrance D. Barrett, Wen Yan, Jamie M. Freedman, Guy Lagaud, Clodagh E. Prendergast, Veronica Moreno, Jayashree Pyati, Katherine Figueroa, Lina Li, Xiaodong Wu, Michele Rizzolio, James G. Breitenbucher, Kelly McClure, and Nigel P. Shankley

Johnson & Johnson Pharmaceutical Research & Development L.L.C., San Diego, California

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.

Received April 17, 2007; accepted July 17, 2007.

Address correspondence to: Dr. Terrance Barrett, Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121. E-mail: tbarret1{at}prdus.jnj.com






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