Discovery and Optimization of Pyrazole Amides as Inhibitors of ELOVL1
Jon H. Come, Timothy J. Senter, Michael P. Clark, John J. Court, Zachary J. Gale-Day, Wenxin Gu, Elaine Krueger, Jianglin Liang, Mark R. Morris, Suganthini Nanthakumar, Hardwin O’Dowd, François Maltais, Ganesh Iyer, John L. Andreassi, Christina Boucher, Tony Considine, Cameron Stuver Moody, W. P. Taylor, A. K. Mohanty, Yu-Lin Huang, Harmon Zuccola, Joyce T. Coll, Kenneth C. Bonanno, Kevin J. Gagnon, Lu Gan, Fan Lü, Hong Gao, Ananthisrinivas Chakilam, Juntyma J. Engtrakul, Bin Song, Daniel K. Crawford, Elisabeth Doyle, Tal Kramer, Bryan W. Vought, Jonathan A. Phillips, Raymond A. Kemper, Martin E. Sanders, Rebecca Swett, Brinley F. Furey, Ray Winquist, Mark E. Bunnage, Katrina L. Jackson, Paul S. Charifson, Sanjay S. P. Magavi
Abstract
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.