title: Nonpeptidic inhibitors of human leukocyte elastase. 2. Design, synthesis, and in vitro activity of a series of 3-amino-6-arylopyridin-2-one trifluoromethyl ketones.
abstract: A series of potent nonpeptidic inhibitors of the enzyme human leukocyte elastase (HLE) is reported. These inhibitors contain a 3-amino-2-pyridone ring as a central template in which the pyridone carbonyl and 3-position NH group are thought to form important hydrogen bonding interactions with the Val-216 residue of HLE. Substitution of the 6-position of the pyridone ring by various alkyl and aryl groups was found to afford increases in the in vitro potency of these inhibitors. A 6-position phenyl group, compound 10f, was found to result in a large increase in binding affinity, which was not obtained when the phenyl group was placed in either the 4- or 5-position of the molecule. Compound 10f was found to have good selectivity for HLE over other proteolytic enzymes, with the exception of bovine pancreatic chymotrypsin (BPC). Substitution of the 6-phenyl group in these molecules was found to decrease binding affinity for BPC without adversely affecting affinity for HLE.
authors.affiliation: Department of Medicinal Chemistry, ZENECA Pharmaceuticals Group, Wilmington, Delaware 19897.
authors.forename: J R
authors.initials: JR
authors.lastname: Damewood
authors.forename: P D
authors.initials: PD
authors.lastname: Edwards
authors.forename: S
authors.initials: S
authors.lastname: Feeney
authors.forename: B C
authors.initials: BC
authors.lastname: Gomes
authors.forename: G B
authors.initials: GB
authors.lastname: Steelman
authors.forename: P A
authors.initials: PA
authors.lastname: Tuthill
authors.forename: J C
authors.initials: JC
authors.lastname: Williams
authors.forename: P
authors.initials: P
authors.lastname: Warner
authors.forename: S A
authors.initials: SA
authors.lastname: Woolson
authors.forename: D J
authors.initials: DJ
authors.lastname: Wolanin
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D019272:Leukocyte Elastase; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014633:Valine / Q000737:chemistry
chemical_list: C089714:2-(3-((benzyloxycarbonyl)amino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide; D000081:Acetamides; D011728:Pyridones; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D014633:Valine