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.
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) = 7.96 +/- 0.11), rat (pK(I) = 8.02 +/- 0.11), and canine (pK(I) = 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 ( approximately 160-, approximately 230-, and approximately 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 (pK(I) = 8.22 +/- 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 +/- 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 ED(50) = 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.
Morton
Magda F
MF
Johnson & Johnson Pharmaceutical Research & Development L.L.C., San Diego, California 92121, USA.
Barrett
Terrance D
TD
Yan
Wen
W
Freedman
Jamie M
JM
Lagaud
Guy
G
Prendergast
Clodagh E
CE
Moreno
Veronica
V
Pyati
Jayashree
J
Figueroa
Katherine
K
Li
Lina
L
Wu
Xiaodong
X
Rizzolio
Michele
M
Breitenbucher
James G
JG
McClure
Kelly
K
Shankley
Nigel P
NP
D000818:Animals; D006224:Cricetinae; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010421:Pentanoic Acids / Q000494:pharmacology*; D010666:Phenylpropionates / Q000378:metabolism / Q000494:pharmacology*; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors* / Q000378:metabolism
C524698:3-(5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-2-m-tolylpropionic acid; D010421:Pentanoic Acids; D010666:Phenylpropionates; D011720:Pyrazoles; D043886:Receptor, Cholecystokinin A; C103490:dexloxiglumide