Synthesis, structure-activity relationships, and pharmacological evaluation of a series of fluorinated 3-benzyl-5-indolecarboxamides: identification of 4-[[5-[((2R)-2-methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methyl indol- 3-yl]methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide, a potent, orally active antagonist of leukotrienes D4 and E4.

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Jacobs RT, Bernstein PR, Cronk LA, Vacek EP, Newcomb LF, Aharony D, Buckner CK, Kusner EJ

J Med Chem. 1994 Apr 29;37(9):1282-97.

PubMed ID

8176706 [ View in PubMed

]

Abstract

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-methyli ndol- 3-yl]methyl]-3-methoxy-N-[(2-methyl-phenyl)sulfonyl]benzamide (38p, ZENECA ZD3523), 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 mumol/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-oxazoli dinone (27) as the key step to establish the chirality of the amide substituent, provided an efficient route for generating 38p in > 99% enantiomeric purity.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Zafirlukast	Cysteinyl leukotriene receptor 1	Ki (nM)	0.34	N/A	N/A	Details