Discovery and SAR of 4-aminopyrrolidine-2-carboxylic acid correctors of CFTR for the treatment of cystic fibrosis
[Display omitted] Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF us...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2022-09, Vol.72, p.128843-128843, Article 128843 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Scanio, Marc J.C. Searle, Xenia B. Liu, Bo Koenig, John R. Altenbach, Robert J. Gfesser, Gregory A. Bogdan, Andrew Greszler, Stephen Zhao, Gang Singh, Ashvani Fan, Yihong Swensen, Andrew M. Vortherms, Timothy Manelli, Arlene Balut, Corina Gao, Wenqing Yong, Hong Schrimpf, Michael Tse, Chris Kym, Philip Wang, Xueqing |
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Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. Herein, we describe the identification and exploration of the SAR of a series of 4-aminopyrrolidine-2-carboxylic acid C2 correctors of CFTR to be used in conjunction with our existing C1 corrector series for the treatment of CF. |
| doi_str_mv | 10.1016/j.bmcl.2022.128843 |
| format | Article |
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Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. Herein, we describe the identification and exploration of the SAR of a series of 4-aminopyrrolidine-2-carboxylic acid C2 correctors of CFTR to be used in conjunction with our existing C1 corrector series for the treatment of CF.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2022.128843</identifier><identifier>PMID: 35688367</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Cystic Fibrosis (CF) ; Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR)</subject><ispartof>Bioorganic & medicinal chemistry letters, 2022-09, Vol.72, p.128843-128843, Article 128843</ispartof><rights>2022 Elsevier Ltd</rights><rights>Copyright © 2022. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-6304e0ba1db19c7dbd1f29af2f396b964e90568cb37390065a7e9bf02cd577783</citedby><cites>FETCH-LOGICAL-c356t-6304e0ba1db19c7dbd1f29af2f396b964e90568cb37390065a7e9bf02cd577783</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X22003195$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35688367$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Scanio, Marc J.C.</creatorcontrib><creatorcontrib>Searle, Xenia B.</creatorcontrib><creatorcontrib>Liu, Bo</creatorcontrib><creatorcontrib>Koenig, John R.</creatorcontrib><creatorcontrib>Altenbach, Robert J.</creatorcontrib><creatorcontrib>Gfesser, Gregory A.</creatorcontrib><creatorcontrib>Bogdan, Andrew</creatorcontrib><creatorcontrib>Greszler, Stephen</creatorcontrib><creatorcontrib>Zhao, Gang</creatorcontrib><creatorcontrib>Singh, Ashvani</creatorcontrib><creatorcontrib>Fan, Yihong</creatorcontrib><creatorcontrib>Swensen, Andrew M.</creatorcontrib><creatorcontrib>Vortherms, Timothy</creatorcontrib><creatorcontrib>Manelli, Arlene</creatorcontrib><creatorcontrib>Balut, Corina</creatorcontrib><creatorcontrib>Gao, Wenqing</creatorcontrib><creatorcontrib>Yong, Hong</creatorcontrib><creatorcontrib>Schrimpf, Michael</creatorcontrib><creatorcontrib>Tse, Chris</creatorcontrib><creatorcontrib>Kym, Philip</creatorcontrib><creatorcontrib>Wang, Xueqing</creatorcontrib><title>Discovery and SAR of 4-aminopyrrolidine-2-carboxylic acid correctors of CFTR for the treatment of cystic fibrosis</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. 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Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. Herein, we describe the identification and exploration of the SAR of a series of 4-aminopyrrolidine-2-carboxylic acid C2 correctors of CFTR to be used in conjunction with our existing C1 corrector series for the treatment of CF.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>35688367</pmid><doi>10.1016/j.bmcl.2022.128843</doi><tpages>1</tpages></addata></record> |
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| source | Elsevier ScienceDirect Journals |
| subjects | Cystic Fibrosis (CF) Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) |
| title | Discovery and SAR of 4-aminopyrrolidine-2-carboxylic acid correctors of CFTR for the treatment of cystic fibrosis |
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