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. Wedeveloped a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorablepharmacokinetics culminating in compound22. Compound22is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesisin ALD patientfibroblasts and lymphocytes in vitro. Compound22reduced C26:0 lysophosphatidyl choline (LPC), a subtype ofVLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels.Compound22is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD

Automated summary

A new selective inhibitor of ELOVL1, compound22, has been discovered as a potential treatment for ALD. This compound demonstrates significant reduction in VLCFA synthesis both in vitro and in a mouse model of the disease.