Journal of Medicinal Chemistry p. 1282 - 1297 (1994)
Update date:2022-07-30
Topics:
Jacobs, Robert T.
Bernstein, Peter R.
Cronk, Laura A.
Vacek, Edward P.
Newcomb, Lisa F.
et al.
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 Ki of 0.42 nM for displacement of <3H>LTD4 on guinea pig lung membranes, a pKB 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.
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