Important Compound Classes
Title
Modulators of Cystic Fibrosis Transmembrane Conductance Regulator
Patent Publication Number
WO 2022/032068 A1
URL
Publication Date
February 10, 2022
Priority Application
US 63/063,194
Priority Date
August 7, 2020
Inventors
Clemens, J. J.; Bookser, B. C.; Cleveland, C.; Coon, T. R.; Gallant, M.; Grootenhuis, P.; Hadida Ruah, S. S.; Laterreur, J.; Melillo, V.; Miller, M. T.; Paraselli, P.; Ramtohul, Y. K.; Reddy, T. J.; Sturino, C.; Valdez, L.; Zhou, J.
Assignee Company
Vertex Pharmaceuticals Incorporated, USA
Disease Area
Cystic fibrosis
Biological Target
CFTR
Summary
Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 83 000 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 lungs 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 the F508del mutation. This mutation occurs in most of the cases of 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 CF. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
X = O, S, SO, SO2
Y = C(Ry)2, O, CO, and
R1 = halogen, C1–C6 alkyl (optionally substituted with 1–6 groups selected from halogen and OH), OR2, N(R2)2, CO2R2, CON(R2)2, CN, phenyl, benzyl, C1–C6 alkoxy, C3–C8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, SO2R2, SR2, SOR2, PO(OR2)2 and PO(R2)2
Z =
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 (nM) are shown in the table below.
Biological Data
The table below shows representative compounds tested for CFTR modulation
and the biological data obtained from testing these representative
examples. For EC50, +++ means <500 nM, ++ means 500
nM–1 μM, and + means >1 μM.
Claims
Total claims: 62
Compound claims: 35
Pharmaceutical composition claims: 13
Method of treatment claims: 13
Use of compound claims: 1
The author declares no competing financial interest.
References
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