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.

ATP结合盒蛋白D1（ATP binding cassette protein D1, ABCD1）缺陷引发的超长链脂肪酸（very long chain fatty acids, VLCFAs）蓄积，被认为是肾上腺脑白质营养不良（adrenoleukodystrophy, ALD）患者出现病理特征的致病基础。本研究基于抑制超长链脂肪酸延伸酶1（elongation of very long chain fatty acid 1 enzyme, ELOVL1）的底物削减策略，开发了一系列噻唑酰胺类化合物，最终得到化合物27——一种活性极强、可穿透中枢神经系统（central nervous system, CNS）且体内药代动力学特性优异的候选化合物。化合物27可选择性抑制ELOVL1活性，能够降低ALD患者成纤维细胞、淋巴细胞与小胶质细胞中C26:0型VLCFAs的合成水平。在ALD小鼠模型中，化合物27给药可使血液中的C26:0型VLCFAs浓度降至接近野生型水平，而在作为疾病相关靶组织的脑组织中，该物质浓度最多可降低65%。针对皮肤、眼部及中枢神经系统的临床前安全性评估结果未阻碍该化合物的研发推进，但此类不良反应的起源与临床相关性仍需进一步研究。综上，抑制ELOVL1是在ALD模型中恢复VLCFAs稳态的有效策略。