Discovery of a novel series of guanidinebenzoates as gut-restricted enteropeptidase and trypsin dual inhibitors for the treatment of metabolic syndrome.

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Tytuł:: Discovery of a novel series of guanidinebenzoates as gut-restricted enteropeptidase and trypsin dual inhibitors for the treatment of metabolic syndrome.
Autorzy:: Zhang X; Discovery Chemistry, Janssen Research and Development, LLC, Spring House, PA, United States. Electronic address: .
Zhu B; Discovery Chemistry, Janssen Research and Development, LLC, Spring House, PA, United States.
Sun W; DPDS Molecular & Cellular Pharmacology, Janssen Research and Development, LLC, Spring House, PA, United States.
Wang M; DPDS Molecular & Cellular Pharmacology, Janssen Research and Development, LLC, Spring House, PA, United States.
Albarazanji K; CVM Discovery, Janssen Research and Development, LLC, Spring House, PA, United States.
Ghosh B; Discovery Chemistry, Janssen Research and Development, LLC, Spring House, PA, United States.
Cummings M; Discovery Chemistry, Janssen Research and Development, LLC, Spring House, PA, United States.
Lenhard J; CVM Discovery, Janssen Research and Development, LLC, Spring House, PA, United States.
Leonard J; CVM Discovery, Janssen Research and Development, LLC, Spring House, PA, United States.
Macielag M; Discovery Chemistry, Janssen Research and Development, LLC, Spring House, PA, United States.
Lanter J; Discovery Chemistry, Janssen Research and Development, LLC, Spring House, PA, United States.
Źródło:: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 May 15; Vol. 40, pp. 127939. Date of Electronic Publication: 2021 Mar 11.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Publication: Oxford : Elsevier Science Ltd
Original Publication: Oxford ; New York : Pergamon Press, c1991-
MeSH Terms:: Benzoates/*pharmacology
Enteropeptidase/*antagonists & inhibitors
Guanidines/*pharmacology
Trypsin Inhibitors/*pharmacology
Animals ; Benzoates/chemical synthesis ; Benzoates/pharmacokinetics ; CHO Cells ; Cattle ; Cricetulus ; Diet, High-Fat ; Feces/chemistry ; Guanidines/chemical synthesis ; Guanidines/pharmacokinetics ; Humans ; Metabolic Syndrome/drug therapy ; Metabolic Syndrome/enzymology ; Mice, Inbred C57BL ; Molecular Structure ; Obesity/drug therapy ; Obesity/enzymology ; Proteins/metabolism ; Structure-Activity Relationship ; Trypsin Inhibitors/chemical synthesis ; Trypsin Inhibitors/pharmacokinetics ; Mice
Contributed Indexing:: Keywords: Enteropeptidase inhibitor; Guanidinebenzoate; Gut-restriction; Trypsin inhibitor
Substance Nomenclature:: 0 (Benzoates)
0 (Guanidines)
0 (Proteins)
0 (Trypsin Inhibitors)
EC 3.4.21.9 (Enteropeptidase)
Entry Date(s):: Date Created: 20210313 Date Completed: 20210921 Latest Revision: 20240226
Update Code:: 20240226
DOI:: 10.1016/j.bmcl.2021.127939
PMID:: 33713780
: Czasopismo naukowe

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A novel series of guanidinebenzoate enteropeptidase and trypsin dual inhibitors has been discovered and SAR studies were conducted. Optimization was focused on improving properties for gut restriction, including increased aqueous solubility, lower cellular permeability, and reduced oral bioavailability. Lead compounds were identified with efficacy in a mouse fecal protein excretion study.
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