Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA)

The C-5 substituted 2,4-diaminoquinazoline
RG3039 (compound 1), a member of a chemical series that
was identified and
optimized using an SMN2 promoter screen, prolongs survival and improves
motor function in a mouse model of spinal muscular atrophy (SMA).
It is a potent inhibitor of the mRNA decapping scavenger enzyme (DcpS),
but the mechanism whereby DcpS inhibition leads to therapeutic benefit
is unclear. Compound 1 is a dibasic lipophilic molecule
that is predicted to accumulate in lysosomes. To understand if the in vivo efficacy is due to DcpS inhibition or other effects
resulting from the physicochemical properties of the chemotype, we
undertook structure based molecular design to identify DcpS inhibitors
with improved physicochemical properties. Herein we describe the design,
synthesis, and in vitro pharmacological characterization
of these DcpS inhibitors along with the in vivo mouse
CNS PK profile of PF-DcpSi (compound 24), one of the
analogs found to be efficacious in SMA mouse model.