Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 10, Pages 4884-4901Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00193
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Funding
- National Institutes of Health Blueprint Neurotherapeutics Program through the National Institute of Neurological Disorders and Stroke
- National Institute on Aging [NS078034]
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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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