Walz Carlo, Spiske Moritz, Walter Magnus, Keller Benjamin-Luca, Mezler Mario, Hoft Carolin, Pohlki Frauke, Vukelić Stella, Hausch Felix
Department Chemistry and Biochemistry, Clemens-Schöpf-Institute, Technical University Darmstadt, Darmstadt 64287, Germany.
Small Molecule Therapeutics and Platform Technologies, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen 67061, Germany.
J Med Chem. 2025 Feb 13;68(3):2639-2656. doi: 10.1021/acs.jmedchem.4c01822. Epub 2025 Jan 22.
In recent years, rationally designed macrocycles have emerged as promising therapeutic modalities for challenging drug targets. Macrocycles can improve affinity, selectivity, and pharmacokinetic (PK) parameters, possibly via providing semirigid, preorganized scaffolds. Nevertheless, how macrocyclization affects PK-relevant properties is still poorly understood. To address this question, we systematically generated and compared 15 matched molecular pairs of macrocycles and structurally similar linear analogs. We found that macrocyclization substantially improves kinetic solubility while not impairing the other measured parameters. We hypothesize that this could arise from "chameleonicity," which was previously reported for large, natural-product-derived macrocycles. Our results show that the improvement of kinetic solubility is an underappreciated aspect of macrocycles that may facilitate formulation strategies compared to linear analogs to improve bioavailability.
近年来，合理设计的大环化合物已成为针对具有挑战性的药物靶点的有前景的治疗方式。大环化合物可以通过提供半刚性、预组织的支架来提高亲和力、选择性和药代动力学（PK）参数。然而，大环化如何影响与PK相关的性质仍知之甚少。为了解决这个问题，我们系统地生成并比较了15对匹配的大环化合物和结构相似的线性类似物分子对。我们发现大环化显著提高了动力学溶解度，同时不损害其他测量参数。我们推测这可能源于“变色龙效应”，这一效应先前已在大型天然产物衍生的大环化合物中报道过。我们的结果表明，动力学溶解度的提高是大环化合物一个未被充分认识的方面，与线性类似物相比，这可能有助于制定提高生物利用度的制剂策略。
