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.

Discovery and Optimization of Pyrazole Amides as Inhibitors of ELOVL1.

Accumulation of very long chain fatty acids (VLCFAs) due to defects in ATP binding cassette protein D1 (ABCD1) is thought to underlie the pathologies observed in adrenoleukodystrophy (ALD). Pursuing a substrate reduction approach based on the inhibition of elongation of very long chain fatty acid 1 enzyme (ELOVL1), we explored a series of thiazole amides that evolved into compound 27─a highly potent, central nervous system (CNS)-penetrant compound with favorable in vivo pharmacokinetics. Compound 27 selectively inhibits ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts, lymphocytes, and microglia. In mouse models of ALD, compound 27 treatment reduced C26:0 VLCFA concentrations to near-wild-type levels in blood and up to 65% in the brain, a disease-relevant tissue. Preclinical safety findings in the skin, eye, and CNS precluded progression; the origin and relevance of these findings require further study. ELOVL1 inhibition is an effective approach for normalizing VLCFAs in models of ALD.

Scalable and efficient synthesis of the mycolactone core.

A highly efficient, scalable, and stereoselective synthesis of the mycolactone core is reported. The synthesis consists of 14 longest linear steps, with 19% overall yield.

A total synthesis of norhalichondrin B.

Four corners: The syntheses of four key building blocks for the total synthesis of norhalichondrin B (see structure) are described. The assembly of these subunits into the natural product is also reported. Key features of the synthesis are the use of the Achmatowicz oxidation/ionic hydrogenation for the synthesis of pyrans and pyranopyrans, and the application of tandem metathesis for the synthesis of pyranopyrans.

A synthesis of the C1-C15 domain of the halichondrins.

A concise route to the C1-C15 domain of the halichondrins is described. The key reaction is the conversion of a furfuryl alcohol to a pyranone. The stereocenter of this pyranone serves as the starting point for the other 8 stereocenters.

Highly functionalized pyranopyrans from furans: a synthesis of the C27-C38 and C44-C53 subunits of norhalichondrin B.

A synthesis of highly functionalized pyranopyrans based on an Achmatowicz oxidation followed by a remarkably diastereoselective Kishi reduction is described in the context of studies directed toward norhalichondrin B.

Synthesis and structure of two new mycolactones isolated from M. ulcerans subsp. shinshuense.

Two new mycolactones, mycolactones S1 and S2, were isolated from culture agar of Mycobacterium ulcerans subsp. shinshuense. Their structures were established in a three-step procedure: (1) probable structures were speculated from MS analysis; (2) candidates were synthesized; (3) HPLC profiles were established for identification of the natural products. Newly isolated mycolactones correspond to the "oxidized forms" of mycolactone A/B, the causative toxin of Buruli ulcer, isolated from Mycobacterium ulcerans.

Heterogeneity in the stereochemistry of mycolactones isolated from M. marinum: toxins produced by fresh vs. saltwater fish pathogens.

A novel mycolactone has been identified from Mycobacterium marinum infecting freshwater fish.