Synthesis and in vitro LTD4 antagonist activity of bicyclic and monocyclic cyclopentylurethane and cyclopentylacetamide N-arylsulfonyl amides.
The dissociation constants (KB) at the LTD4 receptor on guinea pig trachea of a series of monocyclic and bicyclic cyclopentylurethane and cyclopentylacetamide N-arylsulfonyl amides have been measured. The KB was found to be remarkably tolerant of changes in the electronic constitution and lipophilicity of the bicyclic ring system (template). Thus, N-[4[[6-[[(cyclopentyloxy)carbonyl]amino]benzimidazol-1- yl]methyl]-3-methoxybenzoyl]benzenesulfonamide (11a) and N-[4-[[5-[[(cyclopentyloxy)carbonyl]amino]benzo[b]thien-3- yl]methyl]-3-methoxybenzoyl]benzene-sulfonamide (25a) had closely similar affinities (pKB, 9.20 and 9.31, respectively; LTE4 as agonist). It has been shown that the hetero-ring of the template need not be aromatic in order to achieve high affinity, since indoline 31 and 2,3-dihydrobenz-1,4-oxazines 37a-c had pKBs greater than 9. Further, it has been shown that an o-aminophenone (see 42 and Figure 3) can function as a template; the template in 42 [see iii] is bicyclic by virtue of the presence of an intramolecular hydrogen bond. In contrast, when the template is a phenyl ring (48), receptor affinity is markedly reduced. These findings support the notion that central bicyclic ring system in this family of peptidoleukotriene antagonists is a molecular feature which helps to preorganize the acylamino and acidic chains and thereby facilitate the molecular recognition event.
Matassa
V G
VG
Department of Medicinal Chemistry, ICI Americas, Wilmington, Delaware 19897.
Brown
F J
FJ
Bernstein
P R
PR
Shapiro
H S
HS
Maduskuie
T P
TP
Cronk
L A
LA
Vacek
E P
EP
Yee
Y K
YK
Snyder
D W
DW
Krell
R D
RD
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D007211:Indoles; D009130:Muscle, Smooth / Q000187:drug effects; D048448:Phenylcarbamates; D011971:Receptors, Immunologic / Q000187:drug effects; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014105:Tosyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D000096926:Benzenesulfonamides
D001562:Benzimidazoles; D007211:Indoles; D048448:Phenylcarbamates; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013449:Sulfonamides; D013876:Thiophenes; D014105:Tosyl Compounds; C065551:N-(4-((5-(((cyclopentyloxy)carbonyl)amino)benzo(b)thien-3-yl)methyl)-3-methoxybenzoyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C065550:N-(4((6-(((cyclopentyloxy)carbonyl)amino)benzimidazol-1-yl)methyl)-3-methoxybenzoyl)benzenesulfonamide; C062735:zafirlukast