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

Abstract

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 (pK I ϭ 7.96 Ϯ 0.11), rat (pK I ϭ 8.02 Ϯ 0.11), and canine (pK I ϭ 7.98 Ϯ 0.04) CCK1 receptors, and it was also highly selective for the CCK1 receptor compared with the CCK2 receptor across the same species (ϳ160-, ϳ230-, and ϳ75-fold, respectively). The high affinity of JNJ-17156516 at CCK1 receptors in vitro was confirmed in radioligand binding studies on fresh human gallbladder tissue (pK I ϭ 8.22 Ϯ 0.05). In a functional in vitro assay of guinea pig gallbladder contraction, JNJ-17156516 behaved as a competitive antagonist, with a pK B value of 8.00 Ϯ 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 Ϫ1 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 ED 50 ϭ 484 nmol kg Ϫ1 . Pharmacokinetic analysis of JNJ-17156516 in rats, revealed that JNJ-17156516 had a half-life of 3.0 Ϯ 0.5 h and a very high bioavailability (108 Ϯ 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.

Role of CCK and potential utility of CCK1 receptor antagonism in the treatment of pancreatitis induced by biliary tract obstruction

“…The observation that caerulein, an ancestral form of CCK with agonist activity at both CCK1 and CCK2 receptors, elevates plasma amylase activity and causes histological damage to the pancreas was the first observation linking CCK and pancreatitis (reviewed by Beglinger, 1999 ). Further studies showed that other CCK receptor agonists, such as CCK8S (the sulphated terminal eight amino acids of CCK; Morton et al , 2007 ), had similar effects and these effects could be blocked by selective, albeit low‐affinity, CCK1 receptor antagonists such as proglumide ( Niederau et al , 1985 , 1986 ). CCK concentrations are elevated in rat models of pancreatitis such as that induced by bile duct occlusion ( Toriumi et al , 1993 ) and intra‐bile duct injection of taurocholic acid ( Ohlsson et al , 2000 ).…”

“…These observations led to the exploration of loxiglumide in clinical trials for the treatment of pancreatitis ( Ochi et al , 1999 ; Shiratori et al , 2002 ). The results of these studies were mixed, potentially because loxiglumide has complex pharmacokinetics ( Persiani et al , 2002 ) and relatively low affinity for the human CCK1 receptor ( Morton et al , 2007 ). Furthermore, these studies included patients who presented with pancreatitis already in its mid‐ to advanced stages.…”

“…We sought to use the recently described selective CCK1 receptor antagonist JNJ‐17156516 (( S )‐(3‐[5‐(3,4‐dichloro‐phenyl)‐1‐(4‐methoxy‐phenyl)‐1 H ‐pyrazol‐3‐yl]‐2‐ m ‐tolyl‐propionic acid) ( Morton et al , 2007 ) to investigate the role of CCK in the initiation of pancreatitis induced by biliary tract obstruction in the rat. JNJ‐17156516 exhibits a high affinity for the human ( pK I =7.96±0.11) and rat CCK1 receptor ( pK I =8.02±0.11) as well as a high bio‐availability (100%) and long half‐life ( t 1/2 =3.0±0.5 h) in the rat ( Morton et al , 2007 ). The experimental model was selected based on its relevance to two clinical conditions where pancreatitis is known to occur: gall stones and pancreatitis induced by endoscopic retrograde cholangiopancreatography.…”

Gastrointestinal dysmotility disorders in critically ill dogs and cats

“…Due to the complexity of GI motility disorders, many novel therapies targeting different receptors are currently under investigation in both human and animal studies. These receptors include type‐2 chloride channel activators, CCK receptor antagonists, guanylate cyclase 2C agonists, and ileal bile acid transporter antagonists . Lubiprostone, a type‐2 chloride channel (CIC‐2) activator, activates chloride receptors located on gut epithelial cells and drives chloride ions into the gut lumen, inducing intestinal fluid secretion and increasing intestinal motility .…”

“…Lubiprostone, a type‐2 chloride channel (CIC‐2) activator, activates chloride receptors located on gut epithelial cells and drives chloride ions into the gut lumen, inducing intestinal fluid secretion and increasing intestinal motility . CCK‐1 (CCK‐1) receptor antagonists, including loxiglumide and dexloxiglumide, have been shown in animal and human studies to have an effect on the colonic muscle and improve colonic transit time . Guanylate cyclase 2C agonists, including linaclotide, bind to guanylate cyclase C receptors in the gut epithelium resulting in a large increase in secretion of chloride, bicarbonate anions, and fluid secretion into the gut thereby enhancing motility .…”