107813-60-5Relevant articles and documents
Optimization of the Quinoline and Substituted Benzyl Moieties of a Series of Phenyltetrazole Leukotriene D4 Receptor Antagonists
Sawyer, J. Scott,Baldwin, Ronald F.,Rinkema, Lynn E.,Roman, Carlos R.,Fleisch, Jerome H.
, p. 1200 - 1209 (2007/10/02)
This report describes the development of a series of highly potent quinoline-based leukotriene D4 (LTD4) receptor antagonists containing an N-benzyl-substituted phenyltetrazole moiety.They were designed to provide both the correct positioning of the acidic function and secondary lipophilic domain required for strong receptor binding.Members of this series possess high activity in blocking LTD4-induced contractions of isolated guinea pig ileum.Compound 32, LY287192 (2-phenyl>-2H-tetrazol-2-yl>methyl>-5-fluorobenzoic acid sodium salt), blocked contraction with a pKB value of 9.1+/-0.3.Qualitative structure-activity studies have demonstrated specific requirements for the best activity.In particular, ortho substitution of the benzyl group with an acidic function was crucial for maximum potency.In cases similar to 32, where the benzyl group possesses an ortho carboxylate, the N-2-substituted tetrazole isomer showed 100-fold greater activity relative to the corresponding N-1 isomer.This pattern was reversed when the acid was substituted at the para position.The quinoline unit may be replaced by other nitrogen-containing heterocycles.
N- Carboxylic Acids, Hydroxamic Acids, Tetrazoles, and Sulfonyl Carboxamides. Potent Orally Active Leukotriene D4 Antagonists of Novel Structure
Musser, John H.,Kreft, Anthony F.,Bender, Reinhold H. W.,Kubrak, Dennis M.,Grimes, David,et al.
, p. 240 - 245 (2007/10/02)
Four series of N- compounds were prepared as leukotriene D4 (LTD4) antagonists.In the hydroxamic acid series, methyl 3-(2-quinolinylmethoxy)benzeneacetohydroxamate (Wy-48,422, 20) was the most potent inhibitor of LTD4-induced bronchoconstriction with an oral ED50 of 7.9 mg/kg.Compound 20 was also orally inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ED50 of 3.6 mg/kg.In vitro, against LTD4-induced contraction of isolated guinea pig trachea pretreated with indomethacin and 1-cysteine, 20 produced a pKB value of 6.08.In the sulfonyl carboxamide series, N--3-(2-quinolinylmethoxy)-benzamide (Wy-49,353, 30) was the most potent antagonist.Compound 30 orally inhibited both LTD4- and ovalbumin-induced bronchoconstriction with ED50s of 0.4 and 20.2 mg/kg, respectively.In vitro, against LTD4-induced contraction of isolated guinea pig trachea, 30 produced a pKB value of 7.78.In the carboxylic acid series, which served as intermediates for the above two series, 3-(2-quinolinylmethoxy)benzeneacetic acid (Wy-46,016, 5) was the most potent inhibitor of LTD4-induced bronchoconstriction (99percent at 25 mg/kg, intraduodenally); however, the pKB for this compound was disappointing (5.79).In the tetrazole series, the most potent inhibitor was 2-methyl>quinoline (Wy-49,451, 41).The respective inhibitory ED50s were 3.0 mg/kg versus LTD4 and 17.5 mg/kg versus ovalbumin.In the isolated guinea pig trachea, 41 produced a pKB value of 6.70.
