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

  • J Med Chem. 2021 Dec 23;64(24):17777-17794. doi: 10.1021/acs.jmedchem.1c00948.
Michael J Boyd  1 Philip N Collier  1 Michael P Clark  1 Hongbo Deng  1 Sarathy Kesavan  1 Steven M Ronkin  1 Nathan Waal  1 Jian Wang  1 Jingrong Cao  1 Pan Li  1 Jon Come  1 Ioana Davies  1 John P Duffy  1 John E Cochran  1 John J Court  1 Kishan Chandupatla  1 Katrina L Jackson  1 Francois Maltais  1 Hardwin O'Dowd  1 Christina Boucher  1 Tony Considine  1 William P Taylor  1 Hong Gao  1 Ananthisrinivas Chakilam  1 Juntyma Engtrakul  1 Dan Crawford  1 Elizabeth Doyle  1 Jonathan Phillips  1 Raymond Kemper  1 Rebecca Swett  1 James Empfield  1 Mark E Bunnage  1 Paul S Charifson  1 Sanjay Shivayogi Magavi  1
Affiliations
  • 1. Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, Massachusetts 02210, United States.
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.

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