154355-75-6

Usage

Uses

Anti-asthmatic; inhibitor (5-lipoxygenase).

Upstream product

• 173095-31-3 C₂₉H₂₂FNO₅S 
• 459-46-1 4-Fluorobenzyl bromide 
• 173095-30-2 4-<5-<(4-fluorophenyl)methyl>-2-thienyl>-3-butyn-2-ol 
• 154355-83-6 2-Bromo-5-(4-fluorophenylmethyl)thiophene 
• 63877-96-3 2-(4-fluorophenylmethyl)thiophene 

Relevant academic research and scientific papers

Substituted arylalkynyl-and heteroarylalkynl-N-hydroxyurea inhibitors of leukotriene biosynthesis

The invention relates to compounds having activity to inhibit lipoxygenase enzyme activity, to pharmaceutical compositions comprising these compounds, and to a medical method of treating. More particularly, this invention concerns certain substituted arylalkynyl- and ((heteroaryl)alkynyl)-N-hydroxy-ureas which inhibit leukotriene biosynthesis, to pharmaceutical compositions of these compounds and to a method of inhibiting leukotriene biosynthesis.

Process for the preparation of N-4-[(substituted phenyl)alkylheterocyclic]-N

A process for preparing a compound of the structure I STR1 where A is oxygen and sulfur and R1 is selected from the group consisting of hydrogen, halogen, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, and trifluoromethyl, and R2 is alkyl of one to four carbon atoms, comprising coupling a compound of formula II: STR2 where X is bromine or iodine, with an N-hydroxyurea compound of formula III: STR3 in the presence of a palladium catalyst followed by reaction of the product thus formed with an alkali metal isocyante. The compounds of formula I are inhibitors of the enzyme 5-lipoxygenase and are thus useful as therapeutic agents for the treatment of allergic and inflammatory disease conditions.

(R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]- N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor

Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5- lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N- hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]- N-hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4- fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene- mediated disorders.

[(SUBSTITUTED) PHENYALKYL]FURYLALKYNYL-AND [SUBSTITUTED)PHENYALKYL]THIENYLALKYNYL-N-HYDROXYUREA INHIBITORS OR LEUKOTRIENE BIOSYNTHESIS

The present invention relates to compounds of the formula and the pharmaceutically acceptable salts thereof wherein Z is selected from optionally substituted phenyl, furyl, thienyl or thiazolyl; which inhibits leukotriene biosynthesis and is useful in the treatment of inflammatory disease states; also disclosed are leukotriene biosynthesis inhibiting compositions and a method for inhibiting 5-lipoxygenase activity and leukotriene biosynthesis