Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1
Michael J. Boyd, Philip N. Collier, Michael P. Clark, Hongbo Deng, Sarathy Kesavan, Steven Ronkin, Nathan D. Waal, Jian Wang, Jingrong Cao, Pan Li, Jon H. Come, Ioana Davies, John P. Duffy, John E. Cochran, John J. Court, Kishan R. Chandupatla, Katrina L. Jackson, François Maltais, Hardwin O’Dowd, Christina Boucher, Tony Considine, W. P. Taylor, Hong Gao, Ananthisrinivas Chakilam, Juntyma J. Engtrakul, Daniel K. Crawford, Elizabeth A. Doyle, Jonathan A. Phillips, Raymond A. Kemper, Rebecca Swett, James Empfield, Mark E. Bunnage, Paul S. Charifson, Sanjay S. P. Magavi
Abstract
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.