ACS Medicinal Chemistry Letters
Page 6 of 8
C.R.H., T.K. drafted and corrected manuscript with input from all
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authors. A.K.V., C.D.A. and S.S. performed the chemical
synthesis and C.R.H. oversaw the medicinal chemistry, target
selection and interpreted the biological data. A.K.V. performed the
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molecular modeling.
A.L.A. and C.E.H. performed the
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macrophage cellular assays and T.K. oversaw the experiments.
S.K. and N.G. performed the PK studies. Y.A. oversaw all of the
PK experiments.
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Funding Sources
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C.R.H. thanks the UNMC College of Pharmacy for start-up funds.
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Stability in Human Hepatocyte S9 Fractions
ACKNOWLEDGMENT
t1/2 (min)
49.4
CLHEP (mL/min/kg)
12.6
ER
0.63
The authors would like to thank Q2 solutions for the in vitro DMPK
experiments, BPS Biosciences for the PDE4 in vitro experiments,
and Frontage Laboratories for the in vivo PK experiments. The
authors would also like to thank Prof. Daryl J. Murry for the high-
resolution mass spectrometry data.
11h
aIn vitro DMPK studies performed at Q2 Solutions,
Indianapolis, IN bIntrinsic and predicted hepatic clearance
based on experiments in liver microsomes. c%fu = % fraction
unbound
ABBREVIATIONS
PDE4, phosphodiesterase 4; Kp, total brain:plasma ratio, T3P,
propylphosphonic anhydride; DIPEA, diisopropylethyl amine,
DMF, dimethylformamide; AUC, area under the curve; TNF,
tumor necrosis factor; ELISA, enzyme-linked immunosorbent
assay; PK, pharmacokinetics; DMPK, drug metabolism and
pharmacokinetics.
Lastly, we profiled 11h against a wider panel of PDE
isoforms (see Supplemental Tables 1) in a radioligand binding
assay for % inhibition at 10 M. 11h was selective against all
of the isoforms tested (<50% inhibition), except PDE3B (87%
inhibiton. In addition, 11h was also tested in the NIMH
Psychoactive Drug Screening Program (PDSP), which tests
compounds against a wide panel of targets (see Suppl. Table
2).19 In this panel, 11h was not active (<50% inhibition) against
all receptors except 5-HT2C (59% inhibition) and 2 (70%
inhibition). However, follow-up IC50 determinations showed
11h was only weakly active (5-HT2c, IC50 >10 M and 2, IC50
= 7.8 M)
In summary, a scaffold-hopping experiment identified a
novel 1H-pyrrolo[2,3-b]pyridine-2-carboxamide series of
PDE4B inhibitors. The compounds display a range of PDE4B
inhibition and selectivity versus PDE4D. In addition, we have
shown using molecular modeling how these compounds
interact with the enzyme. We have also shown that our
compounds are equipotent with rolipram in cellular assays
inhibiting macrophage pro-inflammatory cytokine activity.
Finally, compounds also show good in vitro PK profiles.
Further optimization and in vivo activity are on-going and will
be reported in due course.
REFERENCES
(1) Houslay, M. D., Schafer, P., Zhang, K. Y. J. Keynote
review: Phosphodiesterase-4 as a therapeutic target. Drug Disc.
Today 2005, 10, 1503-1519.
(2) Sakkas, L. I., Mavropoulos, A., Bogdanos, D. P.
Phosphodiesterase 4 inhibitors in immune-mediated diseases:
mode of action, clinical applications, current and future
perspectives. Curr. Med. Chem. 2017, 24, 3054-3067.
(3) Fertig, B. A., Baillie, G. S. PDE4-mediated cAMP
signalling. J. Cardiovasc. Dev. Dis. 2018, 5, 8.
(4)
Ahmad, F., Murata, T., Simizu, K., Degerman, E.,
D., Manganiello, V. Cyclic nucleotide
important signaling modulators and
therapeutic targets. Oral Dis. 2015, 21, e25-e50.
(5) Wu, Y., Li, Z., Huang, Y.-Y., Wu, D., Luo, H.-B. Novel
Maurice,
phosphodiesterases:
ASSOCIATED CONTENT
Supporting Information
phosphodiesterase inhibitors for cognitive improvement in
The Supporting Information is available free of charge on the ACS
Publications website.
Alzheimer’s disease. J. Med. Chem. 2018, 61, 5467-5483.
(6)
Savai, R., Pullamsetti, S. S., Banat, G.-A., Weissmann,
General methods for the synthesis and characterization of all
compounds, methods for the cellular assay and selectivity data
(PDF)
N., Ghofrani, A., Grimminger, F., Schermuly, R. T. Targeting
cancer with phosphodiesterase inhibitors. Expert Opin. Investig.
Drugs 2010, 19, 117-131.
AUTHOR INFORMATION
Corresponding Author
(7)
Heckman, P. R. A., Blokland, A., Bollen, E. P. P.,
Prickaerts, J. Phosphodiesterase inhibition and modulation of
corticostriatal and hippocampal circuits: clinical overview and
translational considerations. Neurosci. Biobehav. Rev. 2018, 87,
233-254.
*Phone: 1 402-559-9729. Fax: 1 402-559-5643. E-mail:
Author Contributions
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