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. 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.

Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.

There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 µM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 µM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.

Laminectomy contributes to cervical spine deformity demonstrated by holographic interferometry.

Multiple factors contribute to the pathogenesis of postlaminectomy deformity and instability of the cervical spine. The complex alterations in both static and dynamic biomechanics after laminectomy are incompletely defined. We sought to examine the role of the lamina in compressive load bearing across the vertebral body. Holographic interferometry was used to study the surface deformation of single axially loaded cervical vertebral bodies before and after hemilaminotomy, hemilaminectomy, and experimental acrylic laminar reconstruction. Our results showed that hemilaminotomy did not alter the surface deformation because of axial loading across the cervical vertebral body. However, gross alterations in surface deformation across the cervical vertebral body were consistently observed after hemilaminectomy. Experimental reconstruction of the laminar arch using acrylic restored the deformation pattern to the prelaminectomized baseline. Our results support a role for the lamina and the integrity of the laminar arch in axial load bearing across the cervical vertebral body. The altered axial load bearing may be a significant contributor to postlaminectomy deformity and instability. These findings offer an additional biomechanical advantage to minimal bony intervention for cervical spine pathology.