2. Academic Validation
  3. Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1

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

Affiliation

  • 1 Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, Massachusetts 02210, United States.
PMID: 34871500 DOI: 10.1021/acs.jmedchem.1c00948
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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