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

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

  • J Med Chem. 2019 May 23;62(10):4884-4901. doi: 10.1021/acs.jmedchem.9b00193.
Mark E Gurney 1,  Richard A Nugent 1,  Xuesheng Mo 1,  Janice A Sindac 1,  Timothy J Hagen 2,  David Fox 3rd 3,  James M O'Donnell 4,  Chong Zhang 4,  Ying Xu 4,  Han-Ting Zhang 5,  Vincent E Groppi 6,  Marc Bailie 7,  Ronald E White 8,  Donna L Romero 9,  A Samuel Vellekoop 10,  Joel R Walker 10,  Matthew D Surman 10,  Lei Zhu 10,  Robert F Campbell 10
Affiliations

Affiliations

  • 1 Tetra Discovery Partners, Inc. , 38 Fulton Street West , Grand Rapids , Michigan 49503 , United States.
  • 2 Department of Chemistry and Biochemistry , Northern Illinois University , 1425 West Lincoln Highway , DeKalb , Illinois 60115 , United States.
  • 3 Beryllium Discovery Corp. , 7869 NE Day Road West , Bainbridge Island , Washington 98110 , United States.
  • 4 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences , University at Buffalo, The State University of New York , Buffalo , New York 14214-8033 , United States.
  • 5 Departments of Behavioral Medicine & Psychiatry and Physiology, Pharmacology & Neuroscience, Rockefeller Neurosciences Institute , West Virginia University Health Sciences Center , 1 Medical Center Drive , Morgantown , West Virginia 26506 , United States.
  • 6 Michigan Drug Discovery, Life Sciences Institute , University of Michigan , 210 Washtenaw Avenue , Ann Arbor , Michigan 48103 , United States.
  • 7 INDS Inc. , 6111 Jackson Road, Suite 100 , Ann Arbor , Michigan 48103 , United States.
  • 8 White Global Pharma Consultants , 31 Kinglet Drive , South Cranbury , New Jersey 08512 , United States.
  • 9 Pharma-Vation Consulting, LLC , 1201 Turnberry Ridge Court , Chesterfield , Missouri 63005 , United States.
  • 10 Albany Molecular Research, Inc. , 21 Corporate Circle , Albany , New York 12203 , United States.
PMID: 31013090 DOI: 10.1021/acs.jmedchem.9b00193
Abstract

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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