Pala Daniele, Ronchi Paolo, Rescigno Donatella, Bertani Barbara, Capelli Anna Maria, Guariento Sara, Marchini Gessica, Milioli Marco, Cesari Nicola, Federico Giuseppina, Grandi Andrea, Stellari Franco F, Fernandez Sergio Xanxo, Pappani Alice, Venturi Luca, Biagetti Matteo, Civelli Maurizio, Semeraro Teresa, Bianchi Federica, Trist Iuni M L, Remelli Rosaria, Armani Elisabetta, Pizzirani Daniela
Chiesi Farmaceutici S.p.A., Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
Aptuit, an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy.
ACS Med Chem Lett. 2024 Oct 23;15(11):1925-1932. doi: 10.1021/acsmedchemlett.4c00374. eCollection 2024 Nov 14.
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 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 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 ADME properties, potentially favoring lung retention. The optimized hits and might thus be considered promising starting points for the development of novel inhaled ALK5 inhibitors.
ALK5抑制剂是治疗包括癌症和纤维化在内的多种病症的一种有吸引力的治疗方法。在此，我们报告了一系列以4,6-二取代哒嗪为核心的新型ALK5调节剂的设计与表征。最初利用可用的基于配体和结构的信息，对一组受限的杂芳族核心进行了基于知识的骨架跳跃探索。随后，对最具活性的结构新颖的命中化合物进行了吸入给药的初步优化，应用物理化学标准以尽量减少全身暴露，从而限制不良副作用的风险。所得抑制剂对ALK5的活性和药物代谢动力学性质显著提高，可能有利于肺部滞留。因此，优化后的命中化合物可能被认为是开发新型吸入式ALK5抑制剂的有前景的起点。
