Pyrazole CCK1 receptor antagonists. Part 2: SAR studies by solid-phase library synthesis and determination of Free–Wilson additivity

Sehon, Clark A.; McClure, Kelly J.; Hack, Michael D.; Morton, Magda F.; Gomez, Laurent; Li, Lina; Barrett, Terrance D.; Shankley, Nigel P.; Breitenbucher, J. Guy

doi:10.1016/j.bmcl.2005.09.041

Cited by 25 publications

(18 citation statements)

References 5 publications

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“…However, although this compound is still reported as being investigated in functional dyspepsia (clinical trials identifier NCT00303264; www. clinicaltrials.gov), it is no longer being developed for IBS, Sehon et al, 2006). This study describes the pharmacological characterization of this compound.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we describe the primary pharmacological characterization of a novel CCK1 receptor antagonist, JNJ-17156516, which was arrived at by medicinal chemistry optimization around a lead molecule identified by high-throughput screening Sehon et al, 2006). JNJ-17156516 expressed high affinity at human, canine, and rat CCK1 receptors, and it behaved as a competitive, surmountable antagonist both in vitro and in vivo using bioassays of gallbladder and duodenal contraction.…”

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confidence: 99%

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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

Morton

Barrett²,

Yan³

et al. 2007

J Pharmacol Exp Ther

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Morton

Barrett²,

Yan³

et al. 2007

J Pharmacol Exp Ther

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“…Compound 16 (Figure 3, Table 2) is one of the most potent derivatives (CCK 1 -R pK i = 8.8) [47,48,213]. Moreover, the same company applying an identical substitution pattern on the imidazole ring obtained a new series of CCK 1 -R antagonists demonstrating that the endocyclic shift of the heteroatoms retains the affinity.…”

Section: Substituted Five-membered Ringsmentioning

confidence: 95%

Twenty years of non-peptide CCK₁receptor antagonists: all that glitters is not gold

Varnavas¹,

Lassiani²

2006

Expert Opinion on Therapeutic Patents

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During the last 20 years, pharmaceutical industry and academic efforts have led to several structurally unrelated classes of non-peptide cholecystokinin-1 receptor (CCK 1 -R) antagonists. Due to the lack of high resolution structure of CCK 1 -R and its peptide ligand, different strategies to design antagonists have been adopted. The rational design, based on conformational studies of the endogenous ligand, has provided the so-called 'peptoid' derivatives and conformationally restricted peptoids, whereas all of the other non-peptide antagonists derived by empirical and/or conventional approaches, including the chemical manipulation of natural products, disconnection strategies and the use of single key amino acids. All of these strategies include a final optimisation step of the obtained lead compound performed by chemical modifications. The CCK 1 -R antagonists, in addition to providing a better characterisation of the CCK 1 -R receptor subtype as pharmacological tools and improving the knowledge of the physiological and pathological role(s) of CCK, may possess therapeutic potential in humans. As the complex biological effects of CCK mediated by CCK 1 -R in the CNS are not yet completely established, the therapeutic potential of these antagonists at present is limited to the gastrointestinal system disorders. Up until now, loxiglumide and its R-enantiomer (dexloxiglumide) along with lintitript are the CCK 1 -R antagonists at the most advanced stage of clinical research in gastroenterology.

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“…There have consequently been numerous reports of solid-phase protocols for preparing pyrazoles from carbonyl derivatives. [54][55][56] Many of these rely on typical schemes that are found in the solution-phase versions. …”

Section: Synthesis Of Pyrazolesmentioning

confidence: 99%

6.13 Use of Carbonyl Derivatives for Heterocyclic Synthesis

Schiltz¹

2014

Comprehensive Organic Synthesis II

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Pyrazole CCK1 receptor antagonists. Part 2: SAR studies by solid-phase library synthesis and determination of Free–Wilson additivity

Cited by 25 publications

References 5 publications

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), a Novel, Potent, and Selective Cholecystokinin 1 Receptor Antagonist: In Vitro and in Vivo Pharmacological Comparison with Dexloxiglumide

Twenty years of non-peptide CCK₁receptor antagonists: all that glitters is not gold

6.13 Use of Carbonyl Derivatives for Heterocyclic Synthesis

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Pyrazole CCK1 receptor antagonists. Part 2: SAR studies by solid-phase library synthesis and determination of Free–Wilson additivity

Cited by 25 publications

References 5 publications

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), a Novel, Potent, and Selective Cholecystokinin 1 Receptor Antagonist: In Vitro and in Vivo Pharmacological Comparison with Dexloxiglumide

Twenty years of non-peptide CCK1receptor antagonists: all that glitters is not gold

6.13 Use of Carbonyl Derivatives for Heterocyclic Synthesis

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Twenty years of non-peptide CCK₁receptor antagonists: all that glitters is not gold