title: Synthesis and elastase-inhibiting activity of 2-pyridinyl-isothiazol-3(2H)-one 1,1-dioxides.
abstract: The synthesis of a series of new isothiazol-3(2H)-one 1,1-dioxides with halogenated (mostly fluorinated) pyridinyl and pentafluorophenyl substituents at 2-position is reported. These compounds (18-24) became easily accessible from 2-thiocyanato-1-carboxaldehydes and aminopyridines, pentafluoroaniline, respectively, by an isothiazolium cyclization-oxidation route. Compound 21 exhibited an IC(50) value of 3.1 microM toward human leukocyte elastase. The proteases cathepsin G, trypsin, cathepsin L, and angiotensin-converting enzyme, and the serine esterases acetylcholinesterase and cholesterol esterase were not inhibited by 21.
authors.affiliation: Institute for Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eilfeld
authors.forename: Camino M
authors.initials: CM
authors.lastname: González Tanarro
authors.forename: Maxim
authors.initials: M
authors.lastname: Frizler
authors.forename: Joachim
authors.initials: J
authors.lastname: Sieler
authors.forename: Bärbel
authors.initials: B
authors.lastname: Schulze
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects; D056649:Cathepsin G; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003500:Cyclization; D003546:Cysteine Endopeptidases; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects; D012697:Serine Endopeptidases; D013237:Stereoisomerism; D002787:Sterol Esterase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000187:drug effects
chemical_list: D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; D002787:Sterol Esterase; D000110:Acetylcholinesterase; D002403:Cathepsins; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase; D014357:Trypsin; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L