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Research ArticleDrug Discovery and Translational Medicine

Mitigation of Off-Target Adrenergic Binding and Effects on Cardiovascular Function in the Discovery of Novel Ribosomal S6 Kinase 2 Inhibitors

Ryan M. Fryer, Akalushi Muthukumarana, Rong Rhonda Chen, James D. Smith, Suzanne Nodop Mazurek, Kyle E. Harrington, Roger M. Dinallo, Jennifer Burke, Frank M. DiCapua, Xin Guo, Thomas M. Kirrane, Roger J. Snow, Yunlong Zhang, Fariba Soleymanzadeh, Jeffrey B. Madwed, Mohammed A. Kashem, Stanley Z. Kugler, Margaret M. O'Neill, Paul C. Harrison, Glenn A. Reinhart and Stephen J. Boyer
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 492-500; DOI: https://doi.org/10.1124/jpet.111.189365
Ryan M. Fryer
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Akalushi Muthukumarana
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Rong Rhonda Chen
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James D. Smith
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Suzanne Nodop Mazurek
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Kyle E. Harrington
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Roger M. Dinallo
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Jennifer Burke
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Frank M. DiCapua
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Xin Guo
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Thomas M. Kirrane
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Roger J. Snow
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Yunlong Zhang
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Fariba Soleymanzadeh
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Jeffrey B. Madwed
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Mohammed A. Kashem
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Stanley Z. Kugler
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Margaret M. O'Neill
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Paul C. Harrison
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Glenn A. Reinhart
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Abstract

We previously reported the discovery of a novel ribosomal S6 kinase 2 (RSK2) inhibitor, (R)-5-Methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a] indole-8-carboxylic acid [1-(3-dimethylamino-propyl)-1H-benzoimidazol-2-yl]-amide (BIX 02565), with high potency (IC50 = 1.1 nM) targeted for the treatment of heart failure. In the present study, we report that despite nanomolar potency at the target, BIX 02565 elicits off-target binding at multiple adrenergic receptor subtypes that are important in the control of vascular tone and cardiac function. To elucidate in vivo the functional consequence of receptor binding, we characterized the cardiovascular (CV) profile of the compound in an anesthetized rat CV screen and telemetry-instrumented conscious rats. Infusion of BIX 02565 (1, 3, and 10 mg/kg) in the rat CV screen resulted in a precipitous decrease in both mean arterial pressure (MAP; to -65 ± 6 mm Hg below baseline) and heart rate (−93 ± 13 beats/min). In telemetry-instrumented rats, BIX 02565 (30, 100, and 300 mg/kg p.o. QD for 4 days) elicited concentration-dependent decreases in MAP after each dose (to −39 ± 4 mm Hg on day 4 at Tmax); analysis by Demming regression demonstrated strong correlation independent of route of administration and influence of anesthesia. Because of pronounced off-target effects of BIX 02565 on cardiovascular function, a high-throughput selectivity screen at adrenergic α1A and α2A was performed for 30 additional RSK2 inhibitors in a novel chemical series; a wide range of adrenergic binding was achieved (0–92% inhibition), allowing for differentiation within the series. Eleven lead compounds with differential binding were advanced to the rat CV screen for in vivo profiling. This led to the identification of potent RSK2 inhibitors (cellular IC50 <0.14 nM) without relevant α1A and α2A inhibition and no adverse cardiovascular effects in vivo.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.189365.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    NHE
    Na+/H+ exchanger
    BIX 02565
    compound 1
    RSK
    ribosomal S6 kinase
    CV
    cardiovascular
    SAR
    structure-activity relationships
    MAP
    mean arterial pressure
    QD
    once per day
    PK/PD
    pharmacokinetic/pharmacodynamic
    CREB
    cAMP response element-binding protein.

  • Received October 21, 2011.
  • Accepted November 23, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleDrug Discovery and Translational Medicine

Discovery of Potent and Selective RSK2 Inhibitors

Ryan M. Fryer, Akalushi Muthukumarana, Rong Rhonda Chen, James D. Smith, Suzanne Nodop Mazurek, Kyle E. Harrington, Roger M. Dinallo, Jennifer Burke, Frank M. DiCapua, Xin Guo, Thomas M. Kirrane, Roger J. Snow, Yunlong Zhang, Fariba Soleymanzadeh, Jeffrey B. Madwed, Mohammed A. Kashem, Stanley Z. Kugler, Margaret M. O'Neill, Paul C. Harrison, Glenn A. Reinhart and Stephen J. Boyer
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 492-500; DOI: https://doi.org/10.1124/jpet.111.189365

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Research ArticleDrug Discovery and Translational Medicine

Discovery of Potent and Selective RSK2 Inhibitors

Ryan M. Fryer, Akalushi Muthukumarana, Rong Rhonda Chen, James D. Smith, Suzanne Nodop Mazurek, Kyle E. Harrington, Roger M. Dinallo, Jennifer Burke, Frank M. DiCapua, Xin Guo, Thomas M. Kirrane, Roger J. Snow, Yunlong Zhang, Fariba Soleymanzadeh, Jeffrey B. Madwed, Mohammed A. Kashem, Stanley Z. Kugler, Margaret M. O'Neill, Paul C. Harrison, Glenn A. Reinhart and Stephen J. Boyer
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 492-500; DOI: https://doi.org/10.1124/jpet.111.189365
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