Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders

Gurney, Mark E.; Nugent, Richard A.; Mo, Xuesheng; Sindac, Janice A.; Hagen, Timothy J.; Fox, David; O’Donnell, James M.; Zhang, Chong; Xu, Ying; Zhang, Han-Ting; Groppi, Vincent E.; Bailie, Marc; White, Ronald E.; Romero, Donna L.; Vellekoop, A. Samuel; Walker, Joel R.; Surman, Matthew D.; Zhu, Lei; Campbell, Robert F.

doi:10.1021/acs.jmedchem.9b00193

Title: Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders

Journal Article · Tue Apr 23 00:00:00 EDT 2019 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.9b00193· OSTI ID:1544866

Gurney, Mark E. ^[1]; Nugent, Richard A. ^[1]; Mo, Xuesheng ^[1];

^[1];

^[2]; Fox, David ^[3]; O’Donnell, James M. ^[4]; Zhang, Chong ^[4]; Xu, Ying ^[4]; Zhang, Han-Ting ^[5]; Groppi, Vincent E. ^[6]; Bailie, Marc ^[7]; White, Ronald E. ^[8]; Romero, Donna L. ^[9]; Vellekoop, A. Samuel ^[10];

^[10]; Surman, Matthew D. ^[10]; Zhu, Lei ^[10]; Campbell, Robert F. ^[10]

Tetra Discovery Partners, Inc., Grand Rapids, MI (United States)
Northern Illinois Univ., DeKalb, IL (United States)
Beryllium Discovery Corp., Bainbridge Island, WA (United States)
State Univ. of New York (SUNY), Buffalo, NY (United States)
West Virginia Univ., Morgantown, WV (United States). Rockefeller Neurosciences Inst.
Univ. of Michigan, Ann Arbor, MI (United States)
INDS Inc., Ann Arbor, MI (United States)
White Global Pharma Consultants, 31 Kinglet Drive, South Cranbury, New Jersey 08512, United States
Pharma-Vation Consulting, LLC, Chesterfield, MO (United States)
Albany Molecular Research, Inc., Albany, NY (United States)

Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: NS078034

OSTI ID:: 1544866

Journal Information:: Journal of Medicinal Chemistry, Vol. 62, Issue 10; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 30 works

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Title: Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders

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