Modulators of the Cystic Fibrosis Transmembrane ... - ACS Publications

Publication Date. April 12, 2018. Priority Application. US 62/405,598. Priority Date. October 07, 2016. Inventors. Altenbach, R. J.; Bogdan, A.; Couty...
0 downloads 0 Views 551KB Size
Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator Protein Robert B. Kargbo* Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States suffer from decreased fertility, while most males with cystic fibrosis are infertile. CFTR has been shown to function as a cAMP-activated chloride channel with a small single channel conductance and a nonrectifying connection. The cAMP/ATP-mediated anion channel is commonly associated with disease processes, which express absorptive and secretory epithelia cell types. There are many reported ATP releases associated with CFTR expression in the cardiac myocytes, human airway epithelial cells, C127 cells, retinal pigment epithelium cells, and red blood cells from normal and CF patients with mechanical stress. CFTR is a member of the ATP-binding cassette (ABC) transporter subfamily, which serves as a cAMP-dependent chloride channel with a unique cytoplasmic regulator. These are guarded by two large transmembrane domains (TMD1 and TMD2) and two intracellular nucleotide binding domains (NBD1 and NBD2). The mutation in the gene causes two distinct defects: a processing defect and a gating defect. The F508del mutation reduces stability of the NBD1 and destabilizes the interactions between the NBD1 and the nucleotidebinding domains, leading to F508del-CFTR retaining in the endoplasmic reticulum (ER). The ABC transporters regulate the transport of a wide variety of pharmacological agents such as anions, xenobiotics, drugs, and so forth. In addition, these transporters also regulate defensive mechanisms like the resistance of malignant cancer cells against chemotherapeutic agents and provide protection against harmful environmental vectors. Consequently, therapeutic agents that modulate ABC transporters may be beneficial in treating diseases and conditions that are mediated and modulated by CFTR protein. Pharmacological therapeutics act directly on mutant CFTR to improve interactions at the interfaces between NBD1 and membrane-spanning domains (MSD1 or MSD2) or stabilize the NBD1 or NBD2 domain. In addition, CFTR modulators may be beneficial for the treatment of secretory diarrheas, which is found in patients with chronic inflammatory bowel disease and acquired immunodeficiency syndrome, where diarrhea could be a dangerous condition. CFTR modulation may be beneficial for other disease areas not directly linked to mutations in CFTR, including chronic obstructive pulmonary disease (COPD), characterized by a progressive and nonreversible airflow blockage, and Sjogren’s syndrome, an autoimmune disease that affects moistureproducing glands throughout the body (eye, mouth, skin, vagina, gut, and so forth). The pyrrolidine substituted compounds in the invention are modulators of the CFRT protein and are useful therapeutics in treating conditions and diseases such as CF.

Downloaded via 80.82.77.83 on June 29, 2018 at 14:16:44 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

Important Compound Classes.

Title. Substituted Pyrrolidines and Their Use in the Treatment of Cystic Fibrosis Patent Application Number. WO 2018/065962 A1 Publication Date. April 12, 2018 Priority Application. US 62/405,598 Priority Date. October 07, 2016 Inventors. Altenbach, R. J.; Bogdan, A.; Couty, S.; De Lemos, E.; Desroy, N.; Duthion, B.; Gfesser, G. A.; Greszler, S. N.; Housseman, C. G.; Koenig, J. R.; Kym, P. R.; Liu, B.; Scanio, M. J.; Searle, X.; Wang, X.; Yeung, M. C.; Zhao, G. Assignee Company. ABBVIE S.A.R.I and GALAPAGOS NV. Disease Area. Cystic Fibrosis Biological Target. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Summary. Cystic fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which lead to abnormality in water and ion transport across epithelial cells. In particular, the deletion of phenylalanine 508 (F508del) in the cystic fibrosis CFTR anion channel causes misfolding and premature degradation of the protein. The activity of CFTR is essential for the maintenance of electrolyte transport throughout the body, including digestive and respiratory tissues. The main symptom of CF is the fluid imbalance in the lungs, which leads to the accumulation of a highly viscous mucopurulent sputum. Majority of patients affected by CF die from pulmonary disease, even though CF affects other areas including the liver, kidneys, pancreas, and intestine. CF is the most common fatal genetic disease in humans, and up to 10 million people in the United States carry a single copy of the defective gene without ill effects. In contrast, an individual with two copies of the CF associated gene suffers from the debilitating fatal effects of CF. In CF patients, endogenous respiratory epithelial CFTR does not enhance chloride and bicarbonate permeability to the epithelial cells in the lung and other tissues; this lead to disruption in the ion and fluid transport. Consequently, mucus and pathogenic agents accumulate in the lung and cause microbial infections that may turn deadly in CF patients. Furthermore, CF patients may also suffer from gastrointestinal and pancreatic problems. Female subjects may © XXXX American Chemical Society

Received: June 16, 2018

A

DOI: 10.1021/acsmedchemlett.8b00273 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters

Patent Highlight

Definitions. A is further substituted ring; L1 is a bond, halogenated C1−2 alkylene, −NH− or −O−; R1 consists of SO2R6, C(O)R6, C(O)O R6, and C(O)N R7 R8; R2 is C(O)OH or a bioisostere; R2A consists of H, C1−C6 alkyl, C1−C6 haloalkyl, and C3−C6 cycloalkyl; R3 consists of C1−C6 alkyl, C3−C6 cycloalkyl, phenyl, 5−6-membered heteroaryl, and so forth; R3A consists of H, C1−C6 alkyl, and C1−C6 alkoxy; R4 consists of L1- C6−C10 aryl, L1−5−11-membered heteroayl, and so forth; R4A consists of H, C1−C6 alkyl, C1−C6 haloalkyl, aryl, L1−5−11-membered heteroayl, and so forth; R5 consists of C6−C10-membered aryl, 5−11-membered heteroayl, 4−6membered monocyclic heterocycle, and so forth. Key Structures.

Recent Review Articles. 1. Zhang, J.; Wang, Y.; Jiang, X.; Chan, H. C. Cell Mol. Life Sci. 2018, 75, 1537. 2. Sheikh, Z.; Ong, H. X.; Pozzoli, M.; Yong, P. M.; Traini, D. Expert Opin. Drug Discovery 2018, 6, 69. 3. Rickert-Zacharias, V.; Schultz, C.; Mall, M. A. Int. J. Environ. Res. Public Health. 2016, 194, 650. 4. Fu, P.; Ebenezer, D. L.; Ha, A. W.; Suryadevara, V.; Harijith, A.; Natarajan, V. J. Cell Biochem. 2018, DOI: 10.1002/jcb.26707.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Robert B. Kargbo: 0000-0002-5539-6343 Notes

The author declares no competing financial interest.

Biological Assay. The Cell Surface Expression-Horse Radish Peroxidase (CSE-HRP) assay was used to screen for small molecules that repair the dysfunction of mutant CFTR. The cellular assay measures the F508delCFTR cell surface expression after correction with test compounds either with or without co-corrector, which was developed in human lung derived from epithelial cell line. The development was done by expressing the F508delCFTR mutation along with a horseradish peroxidase (HRP) and, after standard manipulations, measure the HRP activity using a luminescence readout (EnVision Multilabel Plate Reader) from these cells. Biological Data. Maximum % activity achieved for the test compounds either with or without a co-corrector at tested concentrations along with respective EC50s calculated. For EC50 (μM) with/without corrector, +++ =