Chemical Society Seminar: Michael Boyd- Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1. Part 2: The Discovery of Pimodivir, a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor of Influenza PB2.

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. Key compounds are selective inhibitors of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Several compounds from this series 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. This series of compounds are a low-molecular-weight, potent ELOVL1 inhibitors that may serve as a useful tools for exploring therapeutic approaches to the treatment of ALD.

Bio:

Michael J. Boyd is a Senior Principal Scientist at Xenon Pharmaceuticals (Boston, MA). He completed his BSc and MSc at Concordia University under the supervision of Prof. Youla Tsantrizos. He first joined Merck-Frosst (Kirkland, PQ) in 1999 where he worked on several projects, including the discoveries of Laropiprant and Odanacatib. He then joined Vertex Pharmaceuticals (Boston, MA) as Director of Chemistry, where he was involved in several key projects, including the discoveries of Pimodivir, a Phase II antiviral drug for the treatment of influenza, and VX-864 (a Phase II drug for the treatment of AAT deficiency). He moved to Xenon Pharmaceuticals in 2021.