Design, Synthesis, and Activity of a Novel Series of Pyridazine-Based ALK5 Inhibitors

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-10-23 DOI:10.1021/acsmedchemlett.4c0037410.1021/acsmedchemlett.4c00374

Daniele Pala, Paolo Ronchi, Donatella Rescigno, Barbara Bertani, Anna Maria Capelli, Sara Guariento, Gessica Marchini, Marco Milioli, Nicola Cesari, Giuseppina Federico, Andrea Grandi, Franco F. Stellari, Sergio Xanxo Fernandez, Alice Pappani, Luca Venturi, Matteo Biagetti, Maurizio Civelli, Teresa Semeraro, Federica Bianchi, Iuni M. L. Trist, Rosaria Remelli, Elisabetta Armani* and Daniela Pizzirani*,

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引用次数: 0

Abstract

ALK5 inhibitors represent an attractive therapeutic approach for the treatment of a variety of pathologies, including cancer and fibrosis. Herein, we report the design and in vitro characterization of a novel series of ALK5 modulators featuring a 4,6-disubstituted pyridazine core. A knowledge-based scaffold-hopping exploration was initially conducted on a restricted set of heteroaromatic cores using available ligand- and structure-based information. The most potent structurally novel hit compound 2A was subsequently subjected to a preliminary optimization for the inhaled delivery, applying physicochemical criteria aimed at minimizing systemic exposure to limit the risk of adverse side effects. The resulting inhibitors showed a marked boost in potency against ALK5 and in vitro ADME properties, potentially favoring lung retention. The optimized hits 20 and 23 might thus be considered promising starting points for the development of novel inhaled ALK5 inhibitors.

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基于哒嗪的新型 ALK5 抑制剂系列的设计、合成和活性

ALK5 抑制剂是治疗癌症和纤维化等多种病症的一种极具吸引力的治疗方法。在此，我们报告了以 4,6-二取代哒嗪为核心的一系列新型 ALK5 调节剂的设计和体外表征。利用现有的配体和结构信息，我们首先对一组受限的杂芳香族核心进行了基于知识的支架跳转探索。随后，对结构最有效的新化合物 2A 进行了吸入给药的初步优化，采用的理化标准旨在最大限度地减少全身暴露，从而限制不良副作用的风险。由此产生的抑制剂对 ALK5 的效力和体外 ADME 特性都有明显提高，可能有利于肺部保留。因此，经过优化的20号和23号化合物可被视为开发新型吸入式ALK5抑制剂的良好起点。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.