Hydroxamic acids and hydroxyureas as novel, selective 5-lipoxygenase inhibitors for possible use in asthma.
Inhibition of 5-lipoxygenase (5-LO) is a potential target for therapeutic intervention in asthma. Acetohydroxamic acids such as BW A4C are potent and selective 5-LO inhibitors in vitro and also inhibit 5-LO activity in vivo following oral administration. In man, BW A4C is metabolised relatively rapidly (t1/2 = approx. 2h) but nevertheless inhibits 5-LO with reasonable persistence. Chemical modification of BW A4C has resulted in compounds, including the alpha-methyl analogues BW B218C and BW A360C and the hydroxyurea BW B70C, that retain high in vitro potency as selective 5-LO inhibitors and, compared to BW A4C, have a higher potency and longer duration of action in vivo. Members of both the hydroxamic acid and hydroxyurea series of 5-LO inhibitors are presently being considered as potential anti-asthma drugs.
Payne
A N
AN
Wellcome Research Laboratories, Kent, U.K.
Jackson
W P
WP
Salmon
J A
JA
Nicholls
A
A
Yeadon
M
M
Garland
L G
LG
D000707:Anaphylaxis / Q000188:drug therapy; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D044482:Benzeneacetamides; D001982:Bronchial Diseases / Q000503:physiopathology; D006168:Guinea Pigs; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D006918:Hydroxyurea / Q000737:chemistry / Q000627:therapeutic use*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*
D044482:Benzeneacetamides; D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; D006918:Hydroxyurea