Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1

In our efforts to identify novel
small molecule inhibitors for
the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput
radiometric screen for inhibitors of elongation of very long chain
fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent,
central nervous system (CNS)-penetrant pyrimidine ether-based compounds
with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing
C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in
vitro. Compound 22 reduced C26:0 lysophosphatidyl choline
(LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter
D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels.
Compound 22 is a low-molecular-weight, potent ELOVL1
inhibitor that may serve as a useful tool for exploring therapeutic
approaches to the treatment of ALD.