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

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.

journal_name

J Med Chem

authors

Gurney ME,Nugent RA,Mo X,Sindac JA,Hagen TJ,Fox D 3rd,O'Donnell JM,Zhang C,Xu Y,Zhang HT,Groppi VE,Bailie M,White RE,Romero DL,Vellekoop AS,Walker JR,Surman MD,Zhu L,Campbell RF

doi

10.1021/acs.jmedchem.9b00193

subject

Has Abstract

pub_date

2019-05-23 00:00:00

pages

4884-4901

issue

10

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

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