Amino hydroxamic acids as potent inhibitors of leukotriene A4 hydrolase.
Leukotriene A4 hydrolase is a zinc-containing enzyme which catalyzes the hydrolysis of LTA4 to LTB4, a proinflammatory mediator. The enzyme also exhibits an aminopeptidase activity. Due to its biological importance, it is of considerable interest to develop selective inhibitors of this enzyme. The design and synthesis of a number of potent beta-amino hydroxylamine and amino hydroxamic acid inhibitors are described here. It was found that having a free amine was essential for high activity. Hydroxylamines were found to be about an order of magnitude less potent than their analogous hydroxamic acids. Our investigation of amino hydroxamic acids as inhibitors of leukotriene A4 hydrolase has led to the development of hydroxamates 16 and 17, which are among the most potent inhibitors found to date. These, compounds were found to be competitive inhibitors with Ki values of 1.6 nM and 3.4 nM respectively, against the peptidase activity. Inhibitor 16 has an IC50 value of < or = 0.15 microM against the epoxide hydrolase activity and is also potent against the production of LTB4 by isolated polymorphonuclear leukocytes (PMNL) activated with ionophore A23187 (IC50 approximately 0.3 microM).
Hogg
J H
JH
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Ollmann
I R
IR
Haeggström
J Z
JZ
Wetterholm
A
A
Samuelsson
B
B
Wong
C H
CH
D001665:Binding Sites / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006098:Granulocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015032:Zinc / Q000378:metabolism
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007476:Ionophores; D000001:Calcimycin; D004851:Epoxide Hydrolases; D015032:Zinc; C043134:leukotriene A4 hydrolase