Challenges of drug discovery in novel target space. The discovery and evaluation of PF-3893787: A novel histamine H4 receptor antagonist

Mowbray, Charles E.; Bell, Andrew S.; Clarke, Nicholas; Collins, Michelle A.; Jones, Rhys; Lane, Charlotte A. L.; Liu, Wai L.; Newman, Sandra D.; Paradowski, Michael; Schenck, Emanuel; Selby, Matthew; Swain, Nigel A.; Williams, D. H.

doi:10.1016/j.bmcl.2011.07.125

Cited by 35 publications

(27 citation statements)

References 20 publications

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“…The compound was also shown to have a pharmacodynamic effect in inhibiting the histamine-induced shape change in eosinophils ex vivo. Similar findings were reported with PF-3893787 another H 4 R antagonist (Mowbray et al, 2011). In the current work the detailed phase 1 clinical safety, pharmacokinetic, and pharmacodynamics data with the selective H 4 R antagonist JNJ-39758979 are presented.…”

Section: Introductionsupporting

confidence: 86%

Clinical and Preclinical Characterization of the Histamine H4 Receptor Antagonist JNJ-39758979

Thurmond

Chen

Dunford

et al. 2014

The Journal of Pharmacology and Experimental Therapeutics

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The histamine H 4 receptor (H 4 R) has been shown to have preclinical involvement in both inflammatory and pruritic responses. JNJ-39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine] is a potent and selective H 4 R antagonist with a K i at the human receptor of 12.5 6 2.6 nM and greater than 80-fold selectivity over other histamine receptors. The compound also exhibited excellent selectivity versus other targets. JNJ-39758979 showed dose-dependent activity in models of asthma and dermatitis consistent with other H 4 R antagonists. Preclinical toxicity studies of up to 6 months in rats and 9 months in monkeys indicated an excellent safety profile, supporting the clinical testing of the compound. An oral formulation of JNJ-39758979 was studied in a phase 1 human volunteer study to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated, with the exception of dose-dependent nausea, and no safety issues were noted in the phase 1 study. JNJ-39758979 exhibited good pharmacokinetics upon oral dosing with a plasma half-life of 124-157 hours after a single oral dose. In addition, dose-dependent inhibition of histamine-induced eosinophil shape change was detected, suggesting that the H 4 R was inhibited in vivo. In conclusion, JNJ-39758979 is a potent and selective H 4 R antagonist that exhibited good preclinical and phase 1 safety in healthy volunteers with evidence of a pharmacodynamics effect in humans.

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Section: Introductionsupporting

confidence: 86%

Clinical and Preclinical Characterization of the Histamine H4 Receptor Antagonist JNJ-39758979

Thurmond

Chen

Dunford

et al. 2014

The Journal of Pharmacology and Experimental Therapeutics

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“…The number of H 3 receptor isoforms possible Vollinga et al (1994). Sharif et al (1996) Data from Harada et al (1983); Gantz et al (1991b); Leurs et al (1994aLeurs et al ( , 1995b; Sharif et al (1996) d Data from Ligneau et al, 2000;Liu et al, 2001b;Morse et al, 2001;Zhu et al, 2001;O'Reilly et al, 2002;Esbenshade et al, 2003;Thurmond et al, 2004Thurmond et al, , 2014aLim et al, 2005;Gbahou et al, 2006;Ligneau et al, 2007;Nagase et al, 2008;Zhao et al, 2008;Deml et al, 2009;Sander et al, 2009;Mowbray et al, 2011;Rossbach et al, 2011;Appl et al, 2012;Shin et al, 2012;Andaloussi et al, 2013;Savall et al, 2014 Fig. 10).…”

Section: A Receptor Structurementioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

Panula

Chazot

Cowart

et al. 2015

Pharmacological Reviews

490

623

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“…In these situations, ex vivo pathway stimulation can be used to enable a pharmacological readout. An illustrative example of an ex vivo PoP biomarker assay for a novel mechanism is the development of a whole blood assay in support of PF-03893787, a selective histamine H4 receptor antagonist [70]. Histamine is an endogenous, short-acting, biogenic amine, which mediates its effect via a family of four G-protein coupled seven transmembrane receptors (H1-4 receptors).…”

Section: Review | Robasmentioning

confidence: 99%

“…A flow cytometry assay in whole blood was designed to measure the cellular shape change associated with chemotaxis using the detection parameters of light forward scatter and the intrinsic autofluorescence of human eosinophils (a gated autofluorescence forward scatter [GAFS] assay) [70]. H4 receptor antagonism was detected by the inhibition of eosinophil shape change induced by the H4 receptor agonist imetit.…”

Section: Review | Robasmentioning

confidence: 99%

Use of Pd Biomarkers to Drive Dose Selection And Early Clinical Decision Making

Robas¹

2012

Bioanalysis

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A major challenge facing the development of new therapies is the high level of compound attrition in late-stage clinical studies. A key factor in reducing these unsustainable levels of attrition is the successful evaluation of the level of drug effect on its target pathway in early development, otherwise known as testing the compound mechanism. Incorporation of PD biomarkers into Phase I/II trials to demonstrate compound binding to its molecular target and the subsequent modulation of downstream pathways enables early testing of compound mechanism and provides a data-driven framework for decisions on compound progression. This review will discuss the identification and validation of such 'fit-for-purpose' PD biomarkers, and case studies illustrating their use and value in dose selection and accelerating the clinical development of small-molecule drugs will be described.

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Challenges of drug discovery in novel target space. The discovery and evaluation of PF-3893787: A novel histamine H4 receptor antagonist

Cited by 35 publications

References 20 publications

Clinical and Preclinical Characterization of the Histamine H4 Receptor Antagonist JNJ-39758979

Clinical and Preclinical Characterization of the Histamine H4 Receptor Antagonist JNJ-39758979

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

Use of Pd Biomarkers to Drive Dose Selection And Early Clinical Decision Making

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