Discovery and development of BI 1265162, an ENaC inhibitor for the treatment of cystic fibrosis.

Autor: Betzemeier B; Boehringer Ingelheim Pharma GmbH & Co. KG, Chemical Development Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany., Braun C; Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany., Sieger P; Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany., Heckel A; Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany., Linz G; Boehringer Ingelheim Pharma GmbH & Co. KG, Chemical Development Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany., Linehan B; Material & Analytical Sciences, Boehringer-Ingelheim, Ridgefield, 06877, Connecticut, USA., Veser T; Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany., Wiedenmayer D; Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany., Kley JT; Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany. Electronic address: joerg.kley@boehringer-ingelheim.com.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Feb 05; Vol. 265, pp. 116038. Date of Electronic Publication: 2023 Dec 18.
DOI: 10.1016/j.ejmech.2023.116038
Abstrakt: Lung selective inhibition of the endothelial sodium channel (ENaC) is a potential mutation agnostic treatment of Cystic Fibrosis (CF). We describe the discovery and development of BI 1265162, the first ENaC inhibitor devoid of the amiloride structural motif that entered clinical trials. The design of BI 1265162 focused on its suitability for inhalation via the Respimat® Soft Mist™ Inhaler and a long duration of action. A convergent and scalable route for the synthesis of BI 1265162 as dihydrogen phosphate salt is presented, that was applied to support clinical trials. A phase 2 study with BI 1265162 did not provide a clear sign of clinical benefit. Whether ENaC inhibition will be able to hold its promise for CF patients remains an open question.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors were employees of Boehringer Ingelheim at the time the research was conducted.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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