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Identification of (R)-6-(1-(4-Cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinic Acid, a Highly Potent and Selective Nonsteroidal Mineralocorticoid Receptor Antagonist

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    Identification of (R)-6-(1-(4-Cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinic Acid, a Highly Potent and Selective Nonsteroidal Mineralocorticoid Receptor Antagonist
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    ∥ Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2014, 57, 10, 4273–4288
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    https://doi.org/10.1021/jm500206r
    Published April 16, 2014
    Copyright © 2014 American Chemical Society
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    Abstract

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    A novel series of nonsteroidal mineralocorticoid receptor (MR) antagonists identified as part of our strategy to follow up on the clinical candidate PF-03882845 (2) is reported. Optimization departed from the previously described pyrazoline 3a and focused on improving the selectivity for MR versus the progesterone receptor (PR) as an approach to avoid potential sex-hormone-related adverse effects and improving biopharmaceutical properties. From this effort, (R)-14c was identified as a potent nonsteroidal MR antagonist (IC50 = 4.5 nM) with higher than 500-fold selectivity versus PR and other related nuclear hormone receptors, with improved solubility as compared to 2 and pharmacokinetic properties suitable for oral administration. (R)-14c was evaluated in vivo using the increase of urinary Na+/K+ ratio in rat as a mechanism biomarker of MR antagonism. Treatment with (R)-14c by oral administration resulted in significant increases in urinary Na+/K+ ratio and demonstrated this novel compound acts as an MR antagonist.

    Copyright © 2014 American Chemical Society

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    This article is cited by 25 publications.

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    14. Anneli Nordqvist, Kenneth L. Granberg. Mineralocorticoid Receptor Antagonists. 2019, 151-188. https://doi.org/10.1016/bs.vh.2018.10.008
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    25. James M. Luther. Is there a new dawn for selective mineralocorticoid receptor antagonism?. Current Opinion in Nephrology and Hypertension 2014, 23 (5) , 456-461. https://doi.org/10.1097/MNH.0000000000000051
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2014, 57, 10, 4273–4288
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm500206r
    Published April 16, 2014
    Copyright © 2014 American Chemical Society
    Request reuse permissions

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