Global Discovery Chemistry, Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
Discovery Sciences, Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
J Med Chem. 2024 Mar 28;67(6):5093-5108. doi: 10.1021/acs.jmedchem.4c00290. Epub 2024 Mar 12.
Leukotriene A4 hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B4 (LTB). Preclinical studies have provided strong evidence that LTA4H is an attractive drug target for the treatment of chronic inflammatory diseases. Here, we describe the transformation of compound , a fragment-like hit, into the potent inhibitor of LTA4H . Our strategy involved two key steps. First, we aimed to increase the polarity of fragment to improve its drug-likeness, particularly its solubility, while preserving both its promising potency and low molecular weight. Second, we utilized structural information and incorporated a basic amino function, which allowed for the formation of an essential hydrogen bond with Q136 of LTA4H and consequently enhanced the potency. Compound exhibited exceptional selectivity and showed oral efficacy in a KRN passive serum-induced arthritis model in mice. The anticipated human dose to achieve 90% target engagement at the trough concentration was determined to be 40 mg administered once daily.
白三烯 A4 水解酶（LTA4H）是促炎白三烯 B4（LTB）生物合成的终末和限速酶。临床前研究为 LTA4H 是治疗慢性炎症性疾病的有吸引力的药物靶点提供了有力证据。在这里，我们描述了将片段样命中化合物 转化为 LTA4H 的强效抑制剂。我们的策略涉及两个关键步骤。首先，我们旨在增加片段的极性以提高其类药性，特别是其溶解度，同时保持其有前途的效力和低分子量。其次，我们利用结构信息并引入碱性氨基功能，这允许与 LTA4H 的 Q136 形成必需的氢键，从而增强了效力。化合物 表现出出色的选择性，并在 KRN 被动血清诱导的关节炎小鼠模型中显示出口服疗效。预计在谷浓度下达到 90%靶标占有率的人体剂量为每天一次给予 40 毫克。
