Bicyclic N-hydroxyurea inhibitors of 5-lipoxygenase: pharmacodynamic, pharmacokinetic, and in vitro metabolic studies characterizing N-hydroxy-N-(2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl)urea.
A series of N-hydroxyurea derivatives have been prepared and examined as inhibitors of 5-lipoxygenase. Oral activity was established by examining the inhibition of LTB4 biosynthesis in an ex vivo assay in the mouse. The pharmacodynamic performance in the mouse of selected compounds was assessed using an ex vivo LTB4 assay and an adoptive peritoneal anaphylaxis assay at extended pretreat times. Compounds with an extended duration of action were re-examined as the individual enantiomers in the ex vivo assay, and the (S) enantiomer of N-hydroxy-N-[2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl]urea, (+)-1a (SB 202235), was selected as the compound with the best overall profile. Higher plasma concentrations and longer plasma half-lives were found for (+)-1a relative to its enantiomer in the mouse, monkey, and dog. In vitro metabolic studies in mouse liver microsomes established enantiospecific glucuronidation as a likely mechanism for the observed differences between the enantiomers of 1a. Enantioselective glucuronidation favoring (-)-1a was also found in human liver microsomes.
Adams
J L
JL
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Garigipati
R S
RS
Sorenson
M
M
Schmidt
S J
SJ
Brian
W R
WR
Newton
J F
JF
Tyrrell
K A
KA
Garver
E
E
Yodis
L A
LA
Chabot-Fletcher
M
M
Tzimas
M
M
Webb
E F
EF
Breton
J J
JJ
Griswold
D E
DE
D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D013237:Stereoisomerism; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D001572:Benzofurans; D016859:Lipoxygenase Inhibitors; C094196:N-hydroxy-N-(2,3-dihydro-6-phenylmethoxy-3-benzofuranyl)urea; D014508:Urea