ACS Medicinal Chemistry Letters
Letter
Garcia, M. L.; Pasternak, A. Discovery of a novel sub-class of ROMK
channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)-
phenyl)acetyl)piperazin-1-yl)ethyl)-isobenzofuran-1(3H)-one. Bioorg.
Med. Chem. Lett. 2013, 23 (21), 5829−5832.
(12) The CV dog model was a Merck internal model used to assess
cardiovascular safety of research compounds.
compound hERG activity, ROMK PD efficacy in acute
rat diuresis model, and derisking off-target activity for
AUTHOR INFORMATION
■
(13) Felix, J. P.; Priest, B. T.; Solly, S.; Bailey, T.; Brochu, R. M.; Liu,
C. J.; Kohler, M. G.; Kiss, L.; Alonso-Galicia, M.; Tang, H.; Pasternak,
A.; Kaczorowski, G. J.; Garcia, M. L. The inwardly rectifying potassium
channel Kir1.1: development of functional assays to identify and
characterize channel inhibitors. Assay Drug Dev. Technol. 2012, 10, 417.
(14) Wang, J.; Della Penna, K.; Wang, H.; Karczewski, J.; Connolly,
T. M.; Koblan, K. S.; Bennett, P. B.; Salata, J. J. Functional and
pharmacological properties of canine ERG potassium channels. Am. J.
Physiol. Heart Circ. Physiol. 2003, 284 (1), H256−267.
(15) The substitution SAR on the phthalide ring was thoroughly
explored, and only small substituents at the C-4 position afforded
compounds with similar ROMK potency and selectivity over hERG.
(16) Bell, I. M.; Bilodeau, M. T. The Impact of Ikr Blockade on
Medicinal Chemistry Programs. Curr. Top. Med. Chem. 2008, 8 (13),
1128−1139.
(17) For a recent review on the role of fluorine in medicinal
chemistry, please see: Gillis, E. P.; Eastman, K. J.; Hill, M. D.;
Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal
Chemistry. J. Med. Chem. 2015, 58 (21), 8315−8359.
(18) Tang, H.; Walsh, S. P.; Yan, Y.; de Jesus, R. K.; Shahripour, A.;
Teumelsan, N.; Zhu, Y.; Ha, S.; Owens, K. A.; Thomas-Fowlkes, B. S.;
Felix, J. P.; Liu, J.; Kohler, M.; Priest, B. T.; Bailey, T.; Brochu, R.;
Alonso-Galicia, M.; Kaczorowski, G. J.; Roy, S.; Yang, L.; Mills, S. G.;
Garcia, M. L.; Pasternak, A. Discovery of Selective Small Molecule
ROMK Inhibitors as Potential New Mechanism Diuretics. ACS Med.
Chem. Lett. 2012, 3 (5), 367−372.
(19) The improvement of hERG off-target activity can be rationalized
by lowering of pKa and compound lipophilicity. Please see the
calculated pKa and LogD.
(20) Compounds 10 and 11 showed similar rat PK properties as
mixture of isomers.
ROMK PD efficacy of compounds 10 and 11.
chiral epoxides.
ROMK PD efficacy of compounds 12, 13, and 16.
(24) Despite of good efficacy in the acute rat diuresis model, meso-
isomer 16 showed quite low aqueous solubility based on qualitative
assessment. In comparison, R,R-isomer 12 has aqueous solubility of at
least 1 mg/mL.
Corresponding Author
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank Junling Gao and Dr. Li-Kang Zhang for help with
HR−MS analysis of key compounds.
ABBREVIATIONS
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ROMK, renal outer medullary potassium channel; hERG, the
Human Ether-a-go-go-Related Gene; PK, pharmacokinetics;
PD, pharmacodynamics; EP, electrophysiology; SHR, sponta-
neous hypertensive rat; HCTZ, hydrochlorothiazide; QD, once
daily; PO, oral dosing
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(26) Only changes in SBP at day 4 are disclosed in this
communication. For a more thorough description of the in vivo
pharmacology of compound 12, a manuscript by Caryn Hampton et al.
will be separately submitted for publication.
(27) Based on internal dose titration, HCTZ achieves approximately
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Bentley, R.; Chen, J.; Shah, K.; Metzger, J.; Forrest, M.; Owens, K.;
Tong, V.; Ha, S.; Roy, S.; Kaczorowski, G. J.; Yang, L.; Parmee, E.;
Garcia, M. L.; Sullivan, K.; Pasternak, A. Discovery of Selective Small
Molecule ROMK Inhibitors as Potential New Mechanism Diuretics.
ACS Med. Chem. Lett. 2015, 6 (7), 747−752 It is worth noting that
most of the SAR work in the mentioned publication was done after the
discovery of MK-7145..
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