Carzaniga Laura, Mazzucato Roberta, Mileo Valentina, Rizzi Andrea, Vallaro Maura, Ermondi Giuseppe, Cattani Silvia, Secchi Andrea, Caron Giulia
Chiesi Farmaceutici, Corporate Preclinical R&D, Research Center, Largo Belloli 11/A, 43122 Parma, Italy.
University of Torino, Molecular Biotechnology and Health Sciences Dept., CASS MedChem, Piazza Nizza 44bis, 10126 Torino, Italy.
ACS Med Chem Lett. 2025 Apr 7;16(5):784-789. doi: 10.1021/acsmedchemlett.4c00611. eCollection 2025 May 8.
Macrocyclization, a well-established strategy for developing ligands against challenging drug targets, was employed to design macrocyclic alternatives to a linear discoidin domain receptor (DDR) inhibitor () with potential applications in treating fibrotic diseases. This study aimed to enhance the drug-like profile of through innovative design strategies encompassing molecular docking and chameleonicity considerations. These efforts resulted in the synthesis of matched pairs of macrocycles differing in flexibility and linker features. Compound emerged as a promising lead, exhibiting nanomolar-range activity, significantly improved solubility, and excellent permeability. Comprehensive experimental physicochemical characterization further highlighted the modest impact of ionization, the major role played by lipophilicity (but not polarity) in driving permeability of the investigated matched pairs, and the limitations of traditional 2D computational descriptors in predicting macrocycle ADME-related properties.
大环化是一种成熟的针对具有挑战性的药物靶点开发配体的策略，被用于设计线性盘状结构域受体（DDR）抑制剂（）的大环类似物，其在治疗纤维化疾病方面具有潜在应用。本研究旨在通过包括分子对接和变色龙效应考量在内的创新设计策略来增强的类药性质。这些努力导致合成了在灵活性和连接子特征上不同的大环匹配对。化合物成为一个有前景的先导化合物，表现出纳摩尔范围的活性、显著改善的溶解度和优异的渗透性。全面的实验物理化学表征进一步突出了离子化的适度影响、亲脂性（而非极性）在驱动所研究的匹配对渗透性方面所起的主要作用，以及传统二维计算描述符在预测大环药物代谢动力学相关性质方面的局限性。
