Targeting the Cystic Fibrosis Transmembrane Conductance Regulator

Jul 12, 2016 - Approximately 90% of the CF patients carry at least one copy of the F508del mutation, and 50%–60% of them are homozygous for this mut...
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Targeting the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein for the Treatment of Cystic Fibrosis Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:

Substituted Tetrahydropyrans and Method of Use

Patent Application Number: US 2016/0122331 A1 Priority Application: US 62/073,586

May 5, 2016 October 31, 2014

Publication date: Priority date:

Inventors:

Kym, P. R.; Wang, X.; Searle, X. B.; Liu, B.; Yeung, M. C.

Applicant:

AbbVie Inc., North Chicago, IL, USA

Disease Area:

Cystic Fibrosis

Summary:

The invention in this patent application relates to tetrahydropyran derivatives represented generally by formula (I) that possess

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein

Biological Target:

activities as modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The compounds may potentially provide useful treatment for cystic fibrosis and other diseases mediated by CFTR. Cystic fibrosis (CF) is a common autosomal recessive genetic disease. It affects nearly every race and ethnicity, but it is most common in the Caucasian population, particularly in North America, Europe, and Australia. Approximately 1 in every 3500 infants born in the United States and 1 in every 3000 infants born in Europe are affected by CF. There are about 75,000 cases of CF worldwide; 30,000 of them are in the United States, and nearly half of the CF patient population is currently 18 years of age and older. Physicians diagnose about 1000 new cases of CF each year, and more than 75% of them are being diagnosed in infants by the age of 2. CF is caused by loss of function mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which is located on chromosome 7. The CFTR protein is a cAMP/ATP-mediated ion channel that is expressed in a variety of cell types, including secretory and absorptive epithelial cells. Normal CFTR protein channels regulate chloride and bicarbonate anion flux through the cell membrane of epithelial cells to maintain electroneutrality and osmolarity across the epithelial membrane. It also regulates the activity of other ion channels and proteins. The activities of CFTR help to regulate fluid and electrolyte balance in epithelial tissues throughout the body, such as those in the lungs, sinuses, pancreas, intestine, reproductive system, and sweat glands. Aberrations in the functions of CFTR result in imbalance of the airway surface liquid, which causes several respiratory disorders such as mucus dehydration, inflammation, recurrent bacterial infection, and irreversible lung damage, which may lead to premature death in affected patients. CF patients also suffer from gastrointestinal problems and pancreatic insufficiency. About 95% of the cystic fibrosis male patients are infertile as a result of azoospermia (absence of sperms in the semen) caused by altered vas deferens, which may be absent, atrophic, or fibrotic. Female CF patients also suffer from decreased fertility due to abnormal cervical mucus. There are about 2000 known mutations in the CFTR gene. The majority of them are extremely rare and do not lead to CF. Only about 125 CFTR mutations have been identified as CF disease-causing mutations. The most common of these mutations is F508del mutation (deletion of a phenylalanine on position 508), which causes defective processing of CFTR in the endoplasmic reticulum (ER). Approximately 90% of the CF patients carry at least one copy of the F508del mutation, and 50% 60% of them are homozygous for this mutation. The defective processing of CFTR causes early CFTR degradation, which leads to reduced trafficking or the absence of the protein on the membrane. Current CF drug discovery efforts are focused on two classes of compounds that can modulate the activities of CFTR. The first class of compounds, referred to as Correctors, can help overcome the defective folding of the mutated CFTR protein to promote its maturation and increase its cell surface expression. The second class of compounds, called Potentiators, may help overcome the defective regulation and/or conductance of the CFTR protein by increasing the probability of channel opening on the membrane surface.

Received:

r XXXX American Chemical Society

A

June 30, 2016

dx.doi.org/10.1021/acsmedchemlett.6b00258 | ACS Med. Chem. Lett. XXXX, XXX, 000–000

ACS Medicinal Chemistry Letters Summary (continued):

PATENT HIGHLIGHT

The modulation of CFTR protein mutations to promote proper protein folding can potentially be beneficial for the treatment of other diseases mediated by CFTR, such as Sj€ogren’s Syndrome (SS), an autoimmune disorder that results in symptoms of xerostomia (dry mouth) and keratoconjunctivitis sicca (KCS, dry eyes). This disease may result from dysregulation of moisture producing glands throughout the body. Another disease that may benefit from modulation of CFTR protein mutations is chronic obstructive lung disease (COLD) or chronic obstructive airway disease (COAD). It is a progressive and irreversible airflow limitation in the airways that results from several physiologic abnormalities, including mucus hypersecretion and impaired mucociliary secretion. Studies have suggested that increasing the anion secretion by CFTR potentiators may help overcome phenotypic complexities with Sj€ogren’s Syndrome by increasing the corneal hydration and by overcoming the impaired mucociliary secretion in COAD. Therefore, there is still a medical need for designing and introducing additional novel compounds able to modulate CFTR such as the compounds disclosed in this patent application that may potentially treat cystic fibrosis and other diseases mediated by aberrant CFTR.

Important Compound Classes:

Key Structures:

The inventors described the synthesis of 76 specific compounds of formula (I), including the following representative examples. Many of the compounds are in racemic forms (rac), and some were resolved as pure enantiomers.

Biological Assay:

Cellular Assays: • Cell Surface Expression-Horse Radish Peroxidase (CSE-HRP) Assay • Transepithelial Clamp Circuit (TECC) on Human Bronchial Epithelial Cells (hBE) Conductance Assay

B

dx.doi.org/10.1021/acsmedchemlett.6b00258 |ACS Med. Chem. Lett. XXXX, XXX, 000–000

ACS Medicinal Chemistry Letters

PATENT HIGHLIGHT

Biological Data:

The biological assay data obtained from the above representative examples are listed in the following table:

Recent Review Articles:

(1.) Heard, A.; Thompson, J.; Carver, J.; Bakey, M.; Wang, X. R. Curr. Drug Targets 2015, 16 (9), 958 964. (2.) Chong, P. A.; Farber, P. J.; Vernon, R. M.; Hudson, R. P.; Mittermaier, A. K.; Forman-Kay, J. D. J. Biol. Chem. 2015, 290 (38), 22862 22878. (3.) Mall, M. A.; Galietta, L. J. V. J. Cystic Fibrosis 2015, 14 (5), 561 570.

’ AUTHOR INFORMATION Corresponding Author

*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail: [email protected]. Notes

The author declares no competing financial interest.

C

dx.doi.org/10.1021/acsmedchemlett.6b00258 |ACS Med. Chem. Lett. XXXX, XXX, 000–000