Novel CFTR Modulators for Treating Cystic Fibrosis

Important Compound Classes

Title

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

Patent Publication Number

WO 2021/030555 A1

Publication Date

February 18, 2021

Priority Application

US 62/886,511

Priority Date

August 14, 2019

Inventors

Anderson, C. D.; Clemens, J. J.; Cleveland, T.; Coon, T. R.; Frieman, B.; Grootenhuis, P.; Hadida Ruah, S. S.; McCartney, J.; Miller, M. T.; Paraselli, P.; Pierre, F.; Swift, S. E.; Zhou, J.

Assignee Company

Vertex Pharmaceutical Incorporated, USA

Disease Area

Cystic fibrosis

Biological Target

Cystic fibrosis transmembrane conductance regulator (CFTR)

Summary

Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70 000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure. In patients with CF, mutations in cystic fibrosis transmembrane conductance regulator (CFTR) endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with CF are infertile and fertility is reduced among females with CF.

Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations. To date, greater than 2000 mutations in the CF gene have been identified. Currently, the CFTR2 database contains information on only 322 of these identified mutations, with sufficient evidence to define 281 mutations as disease causing. The most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as F508del mutation. This mutation occurs in most of the cases with CF.

CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelial cells, where it regulates anion flux across the membrane as well as activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body including respiratory and digestive tissue.

The present application describes a series of novel CFTR modulators for the treatment of cystic fibrosis. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = Si(R)₃, −(O)_n–(C₁–C₈ alkyl), −(O)_n–(C₃–C₁₀ cycloalkyl), wherein n = 0 or 1,

each C₁–C₈ alkyl is substituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy, oxo, C₃–C₁₀ cycloalkyl, C₁–C₄ haloalkyl, and Si(R)₃ groups,

each C₃–C₁₀ cycloalkyl is substituted with 0, 1, 2, 3, or 4 groups selected from halogen, C₁–C₄ haloalkyl, C₁–C₄ alkyl, and Si(R)₃ groups, and

one −CH₂– in each C₁–C₈ alkyl is optionally replaced with −Si(R)₂–;

Y = H and Si(R)₃;

Z = −CH₂– and −Si(R)₂–; and

each R is independently selected from phenyl and C₁–C₆ alkyl groups; and

wherein the compound contains at least one Si atom.

Key Structures

Biological Assay

The bioactivity assay was performed. The compounds described in this application were tested for their ability to modulate CFTR. The EC₅₀ (μM) are shown in the following Table.

Biological Data

The Table below shows representative compounds were tested for CFTR modulation. The biological data obtained from testing representative examples are listed in the following Table.

For EC₅₀: “+++” means <1 μM; “++” means 1–3 μM; “+” means >3 μM.

Claims

Total claims: 27

Compound claims: 16

Pharmaceutical composition claims: 6

Method of treatment claims: 5

Recent Review Articles

• 1.Ramos K. J.; Pilewski J. M.; Taylor-Cousar J. L.. J. Cystic Fibrosis 2021, in press. 10.1016/j.jcf.2021.01.007.
• 2.Amaral M. D.Eur. J. Med. Chem. 2021, 210, 112989.
• 3.Konrad J.; Eber E.; Stadlbauer V.. Paediatr. Respir. Rev. 2021, in press. 10.1016/j.prrv.2020.12.001.
• 4.Dave K.; Dobra R.; Scott S.; Saunders C.; Matthews J.; Simmonds N. J.. Pediatr. Pulmonol. 2021, 56 ( (S1 Suppl.), ), S79.
• 5.Hough N. E.; Chapman S. J.; Flight W. G.. Paediatr. Respir. Rev. 2020, 35, 90.
• 6.Savant A. P.; McColley S. A.. Pediatr. Pulmonol. 2020, 55, 3236.

The author declares no competing financial interest.