SYNTHESIS, STRUCTURE-ACTIVITY-RELATIONSHIPS, AND PHARMACOLOGICAL EVALUATION OF A SERIES OF FLUORINATED 3-BENZYL-5-INDOLECARBOXAMIDES - IDENTIFICATION OF ]-3-METHOXY-N-[(2-METHYLPHENYL)SULFONYL]BENZAMIDE, A POTENT, ORALLY-ACTIVE ANTAGONIST OF LEUKOTRIENES D(4) AND E(4)

The continued exploration of a series of 3-(arylmethyl)-1H-indole-5-ca rboxamides by the introduction of fluorinated amide substituents has r esulted in the discovery of l]-3-methoxy-N-[(2-methylphenyl)sulfonyl]b enzamide (38p, ZENECA ZD 3523),which has been chosen for clinical eval uation. This compound exhibited a K-i of 0.42 nM for displacement of [ H-3]LTD(4) on guinea pig lung membranes, a pK(B) Of 10.13 +/- 0.14 ver sus LTE(4) on guinea pig trachea, and an oral ED(50) Of 1.14 mu mol/kg opposite LTD(4)-induced bronchoconstriction in guinea pigs. The R ena ntiomer was found to be modestly more potent than the S enantiomer 38o . Modification of the amide substituent to afford achiral compounds wa s unsuccessful in achieving comparable levels of activity. Profiling o f 38p opposite a variety of functional assays has demonstrated the sel ectivity of this compound as a leukotriene receptor antagonist. The en antioselective synthesis of 38p, which employed a diastereoselective a lkylation of -trifluorobutyl)-4-methyl-5-phenyl-2-oxazolidinone (27) a s the key step to establish the chirality of the amide substituent, pr ovided an efficient route for generating 38p in >99% enantiomeric puri ty.