Pharmacological Characterization of 2-Methyl-<i>N</i>-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a High-Affinity Antagonist Selective for κ-Opioid Receptors

Grimwood, Sarah; Lu, Yifeng; Schmidt, Anne W.; Vanase-Frawley, Michelle; Sawant-Basak, Aarti; Miller, Emily; McLean, Stafford; Freeman, Jody; Wong, Sharon; McLaughlin, Jay P.; Verhoest, Patrick R.

doi:10.1124/jpet.111.185108

Cited by 54 publications

(55 citation statements)

References 35 publications

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“…1), for the treatment of depression (14). Proof of mechanism (POM) was assessed via a challenge study which employed the agonist spiradoline (U62,066E).…”

Section: Introductionmentioning

confidence: 99%

Quantitative PK–PD Model-Based Translational Pharmacology of a Novel Kappa Opioid Receptor Antagonist Between Rats and Humans

Chang

Byon

et al. 2011

AAPS J

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Abstract. Pharmacokinetic-pharmacodynamic (PK-PD) modeling greatly enables quantitative implementation of the "learn and confirm" paradigm across different stages of drug discovery and development. This work describes the successful prospective application of this concept in the discovery and early development of a novel κ-opioid receptor (KOR) antagonist, PF-04455242, where PK-PD understanding from preclinical biomarker responses enabled successful prediction of the clinical response in a proof of mechanism study. Preclinical data obtained in rats included time course measures of the KOR antagonist (PF-04455242), a KOR agonist (spiradoline), and a KOR-mediated biomarker response (prolactin secretion) in plasma. Clinical data included time course measures of PF-04455242 and prolactin in 24 healthy volunteers following a spiradoline challenge and single oral doses of PF-04455242 (18 and 30 mg). In both species, PF-04455242 successfully reversed spiradoline-induced prolactin response. A competitive antagonism model was developed and implemented within NONMEM to describe the effect of PF-04455242 on spiradoline-induced prolactin elevation in rats and humans. The PK-PD model-based estimate of K i for PF-04455242 in rats was 414 ng/mL. Accounting for species differences in unbound fraction, in vitro K i and brain penetration provided a predicted human K i of 44.4 ng/mL. This prediction was in good agreement with that estimated via the application of the proposed PK-PD model to the clinical data (i.e., 39.2 ng/mL). These results illustrate the utility of the proposed PK-PD model in supporting the quantitative translation of preclinical studies into an accurate clinical expectation. As such, the proposed PK-PD model is useful for supporting the design, selection, and early development of novel KOR antagonists.

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“…1), for the treatment of depression (14). Proof of mechanism (POM) was assessed via a challenge study which employed the agonist spiradoline (U62,066E).…”

Section: Introductionmentioning

confidence: 99%

Quantitative PK–PD Model-Based Translational Pharmacology of a Novel Kappa Opioid Receptor Antagonist Between Rats and Humans

Chang

Byon

et al. 2011

AAPS J

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“…In addition to the original selective -antagonists nor-BNI and JDTic, several other compounds have recently been synthesized Buezo et al, 2010;Mitch et al, 2010;Grimwood et al, 2011). Comparison of these compounds shows that the -antagonists have significant structural differences, considerable structural flexibility, and few overall common features (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…To assess the validity and generality of the hypothesis that long duration of antagonism was a consequence of JNK activation, we examined the properties of this wide range of available ligands reported to produce selective -opioid antagonism (Portoghese et al, 1987;Carroll et al, 2004Carroll et al, , 2006Cueva et al, 2009;Grimwood et al, 2011). In this analysis, we find that for 12 structurally different -antagonists, stimulation of phospho-JNK-immunoreactivity (ir), in spinal cords of antagonist-injected mice and in KOPr-transfected HEK293 cells treated with antagonist in vitro, is strongly correlated with in vivo duration of antagonism of U50,488-induced analgesia.…”

Section: Introductionmentioning

confidence: 99%

“…The diaryl ethers include FP3FBZ [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide] ; JSPA0658 [(S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide] [previously referred to as LY-DMPF (Peters et al, 2011); also known as LY2456302 (Buezo et al, 2010)]; and JSPA071B, [(S)-3-fluoro-4-(4-((2-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide]. biphenyl-4-yl)methyl)propan-1-amine] (Grimwood et al, 2011) was used.…”

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confidence: 99%

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Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

et al. 2011

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The -opioid receptor is a widely expressed G-protein-coupled receptor that has been implicated in biological responses to pain, stress, anxiety, and depression, and its potential as a therapeutic target in these syndromes is becoming increasingly apparent. However, the prototypical selective -opioid antagonists have very long durations of action that have been attributed to c-Jun N-terminal kinase (JNK) 1 activation in vivo. To test generality of this proposed noncompetitive mechanism, we used C57BL/6 wild type mice to determine the durations of antagonist action of novel -opioid receptor ligands and examined their efficacies for JNK1 activation compared with conventional competitive antagonists. Of the 12 compounds tested, 5 had long durations of action that positively correlated with JNK activation: , and naloxone. After long-acting antagonist treatment, pJNK-ir did not increase in mice lacking the -opioid receptor; increased pJNK-ir returned to baseline by 48 h after treatment; and a second challenge with nor-BNI 72 h after the first did not increase pJNK-ir. Long-lasting antagonism and increased phospho-JNK-ir were not seen in animals lacking the JNK1 isoform. These results support the hypothesis that the duration of action of small molecule -opioid receptor antagonists in vivo is determined by their efficacy in activating JNK1 and that persistent inactivation of the -receptor does not require sustained JNK activation.

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“…However, the prototypical KOP receptor-selective non-peptide antagonists nor-BNI, 5′-guanidinylnaltrindole (GNTI) and JDTic exhibit exceptionally long activity, antagonizing KOP receptors for weeks after a single dose (Metcalf and Coop, 2005;). This profile could potentially complicate their use as pharmacological tools and as possible therapeutic agents, spurring the search for shorter acting KOP receptor-selective antagonists (Brugel et al, 2010;Runyon et al, 2010;Grimwood et al, 2011;Peters et al, 2011;Frankowski et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Alanine analogues of [D‐Trp]CJ‐15,208: novel opioid activity profiles and prevention of drug‐ and stress‐induced reinstatement of cocaine‐seeking behaviour

Aldrich

Senadheera

Ross

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe novel macrocyclic peptide cyclo [Phe-D-Pro-Phe-D-Trp] ([D-Trp]CJ-15,208) exhibits κ opioid (KOP) receptor antagonist activity in both in vitro and in vivo assays. The four alanine analogues of this peptide were synthesized and characterized both in vitro and in vivo to assess the contribution of different amino acid residues to the activity of [D-Trp]CJ-15,208. EXPERIMENTAL APPROACHThe peptides were synthesized by a combination of solid phase peptide synthesis and cyclization in solution. The analogues were evaluated in vitro in receptor binding and functional assays, and in vivo with mice using a tail-withdrawal assay for antinociceptive and opioid antagonist activity. Mice demonstrating extinction of cocaine conditioned-place preference (CPP) were pretreated with selected analogues to evaluate prevention of stress or cocaine-induced reinstatement of CPP. KEY RESULTSThe alanine analogues displayed pharmacological profiles in vivo distinctly different from [D-Trp]CJ-15,208. While the analogues exhibited varying opioid receptor affinities and κ and μ opioid receptor antagonist activity in vitro, they produced potent opioid receptor-mediated antinociception (ED50 = 0.28-4.19 nmol, i.c.v.) in vivo. Three of the analogues also displayed KOP receptor antagonist activity in vivo. Pretreatment with an analogue exhibiting both KOP receptor agonist and antagonist activity in vivo prevented both cocaine-and stress-induced reinstatement of cocaine-seeking behaviour in the CPP assay in a time-dependent manner. CONCLUSIONS AND IMPLICATIONSThese unusual macrocyclic peptides exhibit in vivo opioid activity profiles different from the parent compound and represent novel compounds for potential development as therapeutics for drug abuse and possibly as analgesics. BJP

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Pharmacological Characterization of 2-Methyl-N-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a High-Affinity Antagonist Selective for κ-Opioid Receptors

Cited by 54 publications

References 35 publications

Quantitative PK–PD Model-Based Translational Pharmacology of a Novel Kappa Opioid Receptor Antagonist Between Rats and Humans

Quantitative PK–PD Model-Based Translational Pharmacology of a Novel Kappa Opioid Receptor Antagonist Between Rats and Humans

Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

Alanine analogues of [D‐Trp]CJ‐15,208: novel opioid activity profiles and prevention of drug‐ and stress‐induced reinstatement of cocaine‐seeking behaviour

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