Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic
As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
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| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 5 vom: 14. März, Seite 3935-3958 |
| Sprache: |
Englisch |
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| Links: |
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| Themen: |
0RH81L854J |
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| Anmerkungen: |
Date Completed 15.03.2024 Date Revised 15.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c02248 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368552756 |
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| 100 | 1 | |a Shurtleff, Valerie W |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Completed 15.03.2024 | ||
| 500 | |a Date Revised 15.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Glutamine |2 NLM | |
| 650 | 7 | |a 0RH81L854J |2 NLM | |
| 650 | 7 | |a Cysteine Endopeptidases |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 650 | 7 | |a Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Amides |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 700 | 1 | |a Layton, Mark E |e verfasserin |4 aut | |
| 700 | 1 | |a Parish, Craig A |e verfasserin |4 aut | |
| 700 | 1 | |a Perkins, James J |e verfasserin |4 aut | |
| 700 | 1 | |a Schreier, John D |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yunyi |e verfasserin |4 aut | |
| 700 | 1 | |a Adam, Gregory C |e verfasserin |4 aut | |
| 700 | 1 | |a Alvarez, Nadine |e verfasserin |4 aut | |
| 700 | 1 | |a Bahmanjah, Soheila |e verfasserin |4 aut | |
| 700 | 1 | |a Bahnck-Teets, Carolyn M |e verfasserin |4 aut | |
| 700 | 1 | |a Boyce, Christopher W |e verfasserin |4 aut | |
| 700 | 1 | |a Burlein, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Cabalu, Tamara D |e verfasserin |4 aut | |
| 700 | 1 | |a Campbell, Brian T |e verfasserin |4 aut | |
| 700 | 1 | |a Carroll, Steven S |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Wonsuk |e verfasserin |4 aut | |
| 700 | 1 | |a de Lera Ruiz, Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Dolgov, Enriko |e verfasserin |4 aut | |
| 700 | 1 | |a Fay, John F |e verfasserin |4 aut | |
| 700 | 1 | |a Fox, Nicholas G |e verfasserin |4 aut | |
| 700 | 1 | |a Goh, Shih Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Hartingh, Timothy J |e verfasserin |4 aut | |
| 700 | 1 | |a Hurzy, Danielle M |e verfasserin |4 aut | |
| 700 | 1 | |a Kelly, Michael J |c 3rd |e verfasserin |4 aut | |
| 700 | 1 | |a Klein, Daniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Klingler, Franca-Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Krishnamurthy, Harini |e verfasserin |4 aut | |
| 700 | 1 | |a Kudalkar, Shalley |e verfasserin |4 aut | |
| 700 | 1 | |a Mayhood, Todd W |e verfasserin |4 aut | |
| 700 | 1 | |a McKenna, Philip M |e verfasserin |4 aut | |
| 700 | 1 | |a Murray, Edward M |e verfasserin |4 aut | |
| 700 | 1 | |a Nahas, Debbie |e verfasserin |4 aut | |
| 700 | 1 | |a Nawrat, Christopher C |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Dongming |e verfasserin |4 aut | |
| 700 | 1 | |a Roecker, Anthony J |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Vijeta |e verfasserin |4 aut | |
| 700 | 1 | |a Shipe, William D |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Taggart, Robert V |e verfasserin |4 aut | |
| 700 | 1 | |a Truong, Quang |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Yin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xiaoyan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhuang, Ningning |e verfasserin |4 aut | |
| 700 | 1 | |a Perlin, David S |e verfasserin |4 aut | |
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| 700 | 1 | |a Howe, John A |e verfasserin |4 aut | |
| 700 | 1 | |a McCauley, John A |e verfasserin |4 aut | |
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