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

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

  • Eur J Med Chem. 2023 Dec 18:265:116038. doi: 10.1016/j.ejmech.2023.116038.
Bodo Betzemeier 1,  Clemens Braun 2,  Peter Sieger 2,  Armin Heckel 3,  Günter Linz 1,  Brian Linehan 4,  Thomas Veser 3,  Dieter Wiedenmayer 3,  Jörg T Kley 5
Affiliations

Affiliations

  • 1 Boehringer Ingelheim Pharma GmbH & Co. KG, Chemical Development Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany.
  • 2 Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Sciences Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany.
  • 3 Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry Germany, Birkendorfer Straße 65, 88397, Biberach an der Riß, Germany.
  • 4 Material & Analytical Sciences, Boehringer-Ingelheim, Ridgefield, 06877, Connecticut, USA.
  • 5 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.
PMID: 38157597 DOI: 10.1016/j.ejmech.2023.116038
Abstract

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.

Keywords

Benzimidazolium; Cystic fibrosis; ENaC inhibitor; Inhalation; Phosphine oxide.

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