Synthesis, Structure-Activity Relationships, and Pharmacological Evaluation of a Series of Fluorinated 3-Benzyl-5-indolecarboxamides: Identification of 4--1-methylindol-3-yl>methyl>-3-methoxy-N-benzamide, ...

Article abstract of DOI:10.1021/jm00035a008

The continued exploration of a series of 3-(arylmethyl)-1H-indole-5-carboxamides by the introduction of fluorinated amide substituents has resulted in the discovery of 4-<<5-<((2R)-2-methyl-4,4,4-trifluorobutyl)carbamoyl>-1-methylindol-3-yl>methyl>-3-methoxy-N-<(2-methylphenyl)sulfonyl>benzamide (38p, ZENECA ZD 3523), which has been chosen for clinical evaluation.This compound exhibited a K_i of 0.42 nM for displacement of <3H>LTD₄ on guinea pig lung membranes, a pK_B of 10.13 +/- 0.14 versus LTE₄ on guinea pig trachea, and an oral ED50 of 1.14 μmol/kg opposite LTD₄-induced bronchoconstriction in guinea pigs.The R enantiomer was found to be modestly more potent than the S enantiomer 38o.Modification of the amide substituent to afford achiral compounds was unsuccessful in achieving comparable levels of activity.Profiling of 38p opposite a variety of functional assays has demonstrated the selectivity of this compound as a leukotriene receptor antagonist.The enantioselective synthesis of 38p, which employed a diastereoselective alkylation of (4R,5S)-3-(1-oxo-4,4,4-trifluorobutyl)-4-methyl-5-phenyl-2-oxazolidinone (27) as the key step to establish the chirality of the amide substituent, provided an efficient route for generating 38p in >99percent enantiomeric purity.