129425-74-7Relevant articles and documents
HETEROCYCLIC COMPOUNDS AND COMPOSITIONS HAVING NEVROPHARMACOLOGICAL POTENTIAL
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, (2008/06/13)
Novel heterocyclic compounds having a structure according to general formula (1), pharmaceutically acceptable acid addition salts and solvates thereof are described as having a pharmacological profile showing potential for treatment ofacute and chronic ne
(Methoxyalkyl)thiazoles: A new series of potent, selective, and orally active 5-lipoxygenase inhibitors displaying high enantioselectivity
Bird,Bruneau,Crawley,Edwards,Foster,Girodeau,Kingston,McMillan
, p. 2176 - 2186 (2007/10/02)
(Methoxyalkyl)thiazoles are novel 5-lipoxygenase (5-LPO) inhibitors that are neither redox agents nor iron chelators. Consideration of a hypothetical model of the enzyme active site led to this series which is exemplified by 1-[3(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propyl methyl ether (2d, ICI211965). 2d inhibits cell-free guinea pig 5-LPO activity, LTC4 synthesis in plasma free mouse macrophages, and LTB4 synthesis in rat and human blood (IC50s 0.1 μM, 8nM, 0.5 μM, and 0.4 μM, respectively) but does not inhibit the synthesis of cyclooxygenase products at concentrations up to 50 μM in macrophages and 100 μM in blood. 2d is orally active in rat (ex vivo ED50 10 mg/kg in blood taken in 1h after dosing). SAR studies show that high in vitro potency requires methoxy, thiazolyl, and naphthyl groups and depends critically on the substitution pattern. (Methoxyalkyl)thiazoles are chiral. Resolution of 1-methoxy-6-(naphth-2-ylmethoxy)-1-(thiazol-2-yl)indan (2j, ICl216800) shows that (+)-2j is 50-150-fold more potent than (-)-2j in in vitro assays. Thus, (methoxyalkyl)thiazoles are a new series of orally active, selective 5-LPO inhibitors and represent the first class of inhibitors in which inhibition is mediated by specific, enantioselective interactions with the enzyme.
