دورية أكاديمية
أعرض في EDS

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

التفاصيل البيبلوغرافية
العنوان: Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.
المؤلفون: Shurtleff VW; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Layton ME; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Parish CA; Merck & Co., Inc., Rahway, New Jersey 07065, United States., Perkins JJ; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Schreier JD; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Wang Y; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Adam GC; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Alvarez N; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States., Bahmanjah S; Merck & Co., Inc., Rahway, New Jersey 07065, United States., Bahnck-Teets CM; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Boyce CW; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Burlein C; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Cabalu TD; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Campbell BT; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Carroll SS; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Chang W; Merck & Co., Inc., Rahway, New Jersey 07065, United States., de Lera Ruiz M; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Dolgov E; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States., Fay JF; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Fox NG; Merck & Co., Inc., Rahway, New Jersey 07065, United States., Goh SL; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Hartingh TJ; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Hurzy DM; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Kelly MJ 3rd; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Klein DJ; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Klingler FM; MSD (U.K.) Limited, London EC2M 6UR, U.K., Krishnamurthy H; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Kudalkar S; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Mayhood TW; Merck & Co., Inc., Rahway, New Jersey 07065, United States., McKenna PM; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Murray EM; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Nahas D; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Nawrat CC; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Park S; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States., Qian D; Viva Biotech Ltd., Shanghai 201318, China., Roecker AJ; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Sharma V; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States., Shipe WD; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Su J; Merck & Co., Inc., Rahway, New Jersey 07065, United States., Taggart RV; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Truong Q; Merck & Co., Inc., Rahway, New Jersey 07065, United States., Wu Y; Viva Biotech Ltd., Shanghai 201318, China., Zhou X; Merck & Co., Inc., Rahway, New Jersey 07065, United States., Zhuang N; Viva Biotech Ltd., Shanghai 201318, China., Perlin DS; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States., Olsen DB; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Howe JA; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., McCauley JA; Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
المصدر: Journal of medicinal chemistry [J Med Chem] 2024 Mar 14; Vol. 67 (5), pp. 3935-3958. Date of Electronic Publication: 2024 Feb 16.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Glutamine*/chemistry , COVID-19*, Humans ; SARS-CoV-2 ; Cysteine Endopeptidases/chemistry ; Inventions ; Protease Inhibitors/pharmacology ; Amides ; Antiviral Agents/pharmacology ; Antiviral Agents/chemistry
مستخلص: 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.
معلومات مُعتمدة: U19 AI171401 United States AI NIAID NIH HHS
المشرفين على المادة: 0RH81L854J (Glutamine)
EC 3.4.22.- (Cysteine Endopeptidases)
0 (Protease Inhibitors)
0 (Amides)
0 (Antiviral Agents)
تواريخ الأحداث: Date Created: 20240216 Date Completed: 20240315 Latest Revision: 20240823
رمز التحديث: 20240823
DOI: 10.1021/acs.jmedchem.3c02248
PMID: 38365209
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.3c02248