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

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.

Therapeutic Role of ELOVL in Neurological Diseases

“…Age-related hypermethylation and ELOVL2 could act as links between early developmental phases and aging. This involvement of ELOVL2 could be further investigated in future clinical and forensic research. , A particular form of ELOVL3 is related to the skin. Studies in mice lacking ELOVL3 demonstrated that ELOVL3 is necessary for the production of neutral lipids in the skin, wherein these mice had significant water-repelling abnormalities, increased trans-epidermal thin-hair coats, water loss, and hyperplastic pilosebaceous systems.…”

“…It decreases C26:0 VLCFA production in fibroblasts and lymphocytes from ALD patients. The compound’s biochemical and cellular activity was found to be further elevated when the pyridine core was switched with a pyrimidine ring using HEK293, an immortalized human embryonic kidney cell line …”

“…The compound's biochemical and cellular activity was found to be further elevated when the pyridine core was switched with a pyrimidine ring using HEK293, an immortalized human embryonic kidney cell line. 88 It was shown that in order to avoid cerebral adrenoleukodystrophy, delay the beginning of the disease, or diminish its severity and development in adrenomyeloneuropathy patients, a 50−75% reduction in C26:0 VLCFAs may be necessary. 89 The researchers reported the identification of powerful, brainpenetrant pyrazole amides (Figure 2) that block VLCFA synthesis in vitro in a variety of cell types, including ALD patient cells, and in vivo in the blood and brain of an ALDprone mouse model.…”

The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy

“…Until present, over 2,700 types of mutations have been identified (2). ABCD1 codes the protein of adenosine 5 -triphosphate (ATP) binding cassette subfamily D member 1, which is located in the peroxisomal membrane to transport the very-long-chain fatty acids (VLCFAs) into peroxisomes for β-oxidation (3). The dysfunctional ABCD1 causes the failure of VLCFA degradation (4,5), leading to the accumulation of VLCFA, especially C:26 and C:24 in tissues and plasma, and damage to organs, particularly in the cerebral white matter, spinal cord, and adrenal cortex (6,7).…”