Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL Journal of Medicinal Chemistry Pub Date : 2025-02-17 DOI:10.1021/acs.jmedchem.4c02897

Gebhard Thoma, Wolfgang Miltz, Rudolf Waelchli, David Orain, Carsten Spanka, Odile Decoret, Romain M. Wolf, Brian Hurley, Atwood K. Cheung, David A. Sandham, Ayako Honda, Ritesh Tichkule, Xin Chen, Tajesh Patel, Nancy Labbe-Giguere, Kian L. Tan, Clayton Springer, John Manchester, Andrew J. Culshaw, Peter Hunt, Honnappa Srinivas, Carlos A. Penno, Sandrine Ferrand, Shin Numao, Ulrich Schopfer, Petra Jäger, Nathalie Wack, Franziska Hasler, Beatrice Urban, Miriam Sindelar, Pius Loetscher, Michael Kiffe, Xiaojun Ren, Paul Nicklin, Kevin White, Khaushik Subramanian, Haoyuan Liu, Ellena J. Growcott, Till A. Röhn

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Abstract

Leukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl leukotriene C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that drive type 2 inflammation, bronchoconstriction, and itch. Thus, LTC4S represents an attractive drug target for the treatment of allergic inflammatory diseases, but to date, no LTC4S inhibitor has been tested in patients. Herein, we disclose the discovery and preclinical profiling of the highly selective, oral LTC4S inhibitor GJG057 (compound 1), which exhibits 20-fold improved potency (IC₅₀ = 44 nM) versus clinical candidate AZD9898 (IC₅₀ = 900 nM) in a human whole blood LTC4 release assay. GJG057 showed efficacy in a murine asthma exacerbation model as well as in a mastoparan-induced skin challenge PK/PD model and was profiled in GLP toxicology studies. Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug. Its potential as a topical drug is currently being evaluated.

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白三烯C4合成酶高效、高选择性抑制剂GJG057的发现

白三烯C4合成酶（LTC4S）是一种介导半胱氨酸白三烯C4 （LTC4）生物合成的谷胱甘肽s -转移酶。半胱氨酸白三烯（CysLTs）是驱动2型炎症、支气管收缩和瘙痒的脂质介质。因此，LTC4S代表了治疗过敏性炎症疾病的一个有吸引力的药物靶点，但迄今为止，还没有LTC4S抑制剂在患者中进行测试。在此，我们披露了高选择性口服LTC4S抑制剂GJG057（化合物1）的发现和临床前分析，在人全血LTC4释放试验中，其效价（IC50 = 44 nM）比临床候选药物AZD9898 （IC50 = 900 nM）提高了20倍。GJG057在小鼠哮喘加重模型和mastoparan诱导的皮肤挑战PK/PD模型中显示出疗效，并在GLP毒理学研究中进行了分析。尽管GJG057具有良好的特性，但它并没有作为口服药物进入临床试验。目前正在评估其作为外用药物的潜力。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.