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.
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.
Jacobs
R T
RT
Department of Medicinal Chemistry, ZENECA Pharmaceuticals Group, Wilmington, Delaware 19897.
Bernstein
P R
PR
Cronk
L A
LA
Vacek
E P
EP
Newcomb
L F
LF
Aharony
D
D
Buckner
C K
CK
Kusner
E J
EJ
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D017999:Leukotriene E4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D007211:Indoles; C087137:Zeneca ZD 3523; D017998:Leukotriene D4; D017999:Leukotriene E4