Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate
Christopher J. Helal
1
,
Eric Arnold
1
,
Tracey Boyden
1
,
C. Chang
1
,
Thomas A. Chappie
2
,
Ethan L Fisher
1
,
Mihaly Hajós
1
,
John F. Harms
2
,
William E. Hoffman
1
,
John M Humphrey
1
,
J. J. Pandit
1
,
Zhijun Kang
1
,
Robin J. Kleiman
1
,
Bethany L Kormos
2
,
Che-Wah Lee
1
,
Jiemin Lu
1
,
Noha Maklad
1
,
LAURA MCDOWELL
1
,
Dina McGinnis
1
,
Rebecca E Oconnor
1
,
Christopher J Odonnell
1
,
Adam Ogden
1
,
Mary Piotrowski
1
,
CHRISTOPHER J. SCHMIDT
2
,
Patricia A. Seymour
1
,
Hirokazu Ueno
1
,
Nichole Vansell
1
,
Patrick R. Verhoest
2
,
Edward X Yang
1
1
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
|
2
Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States
|
Publication type: Journal Article
Publication date: 2018-01-16
scimago Q1
wos Q1
SJR: 1.801
CiteScore: 11.5
Impact factor: 6.8
ISSN: 00222623, 15204804
PubMed ID:
29293004
Drug Discovery
Molecular Medicine
Abstract
Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (Cav,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan.
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Total citations:
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Citations from 2025:
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GOST
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Helal C. J. et al. Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 3. pp. 1001-1018.
GOST all authors (up to 50)
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Helal C. J., Arnold E., Boyden T., Chang C., Chappie T. A., Fisher E. L., Hajós M., Harms J. F., Hoffman W. E., Humphrey J. M., Pandit J. J., Kang Z., Kleiman R. J., Kormos B. L., Lee C., Lu J., Maklad N., MCDOWELL L., McGinnis D., Oconnor R. E., Odonnell C. J., Ogden A., Piotrowski M., SCHMIDT C. J., Seymour P. A., Ueno H., Vansell N., Verhoest P. R., Yang E. X. Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 3. pp. 1001-1018.
Cite this
RIS
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TY - JOUR
DO - 10.1021/acs.jmedchem.7b01466
UR - https://doi.org/10.1021/acs.jmedchem.7b01466
TI - Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate
T2 - Journal of Medicinal Chemistry
AU - Helal, Christopher J.
AU - Arnold, Eric
AU - Boyden, Tracey
AU - Chang, C.
AU - Chappie, Thomas A.
AU - Fisher, Ethan L
AU - Hajós, Mihaly
AU - Harms, John F.
AU - Hoffman, William E.
AU - Humphrey, John M
AU - Pandit, J. J.
AU - Kang, Zhijun
AU - Kleiman, Robin J.
AU - Kormos, Bethany L
AU - Lee, Che-Wah
AU - Lu, Jiemin
AU - Maklad, Noha
AU - MCDOWELL, LAURA
AU - McGinnis, Dina
AU - Oconnor, Rebecca E
AU - Odonnell, Christopher J
AU - Ogden, Adam
AU - Piotrowski, Mary
AU - SCHMIDT, CHRISTOPHER J.
AU - Seymour, Patricia A.
AU - Ueno, Hirokazu
AU - Vansell, Nichole
AU - Verhoest, Patrick R.
AU - Yang, Edward X
PY - 2018
DA - 2018/01/16
PB - American Chemical Society (ACS)
SP - 1001-1018
IS - 3
VL - 61
PMID - 29293004
SN - 0022-2623
SN - 1520-4804
ER -
Cite this
BibTex (up to 50 authors)
Copy
@article{2018_Helal,
author = {Christopher J. Helal and Eric Arnold and Tracey Boyden and C. Chang and Thomas A. Chappie and Ethan L Fisher and Mihaly Hajós and John F. Harms and William E. Hoffman and John M Humphrey and J. J. Pandit and Zhijun Kang and Robin J. Kleiman and Bethany L Kormos and Che-Wah Lee and Jiemin Lu and Noha Maklad and LAURA MCDOWELL and Dina McGinnis and Rebecca E Oconnor and Christopher J Odonnell and Adam Ogden and Mary Piotrowski and CHRISTOPHER J. SCHMIDT and Patricia A. Seymour and Hirokazu Ueno and Nichole Vansell and Patrick R. Verhoest and Edward X Yang},
title = {Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate},
journal = {Journal of Medicinal Chemistry},
year = {2018},
volume = {61},
publisher = {American Chemical Society (ACS)},
month = {jan},
url = {https://doi.org/10.1021/acs.jmedchem.7b01466},
number = {3},
pages = {1001--1018},
doi = {10.1021/acs.jmedchem.7b01466}
}
Cite this
MLA
Copy
Helal, Christopher J., et al. “Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate.” Journal of Medicinal Chemistry, vol. 61, no. 3, Jan. 2018, pp. 1001-1018. https://doi.org/10.1021/acs.jmedchem.7b01466.