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ICI 204,219 (4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-ylmethy l)-3- methoxy-N-o-tolylsulfonylbenzamide) was designed as a peptide leukotriene (LT) antagonist. The compound is a competitive antagonist of LTD4- and LTE4-induced contraction of guinea pig lung tracheal and parenchymal strips with an apparent negative log molar dissociation constant (KB)(More)
It has been demonstrated that leukotriene (LT)C4 is metabolized to LTD4 via the action of the enzyme gamma-glutamyl transpeptidase. LTD4 is, in turn, converted by the enzyme aminopeptidase to LTE4. In the present study, the pharmacological effects of the aminopeptidase inhibitor, L-cysteine and the gamma-glutamyl transpeptidase inhibitor, L-serine borate,(More)
The actions of the peptide leukotrienes (LT) LTC4, LTD4 and LTE4 and phenylephrine (PE) were studied in isolated left branches of the guinea-pig pulmonary artery (GPPA). Indomethacin 5 x 10(-6) M enhanced both the potency and maximal response of all agonists, but the effect on LTD4 and LTE4 was larger. The influence of indomethacin suggests the release of(More)
Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency(More)
Functional cDNA clones for hamster neurokinin-2 receptor (NK-2R) were isolated from hamster urinary bladder using a polymerase chain reaction-based methodology. The hamster NK-2R consists of 384 amino acids with a relative molecular weight of 43,418. Hamster NK-2R shares significant amino acid sequence homology with other tachykinin receptors, particularly(More)
Using the novel ligand [4,5-3H-Leu9]neurokinin A ([4,5-3H-Leu9] NKA) in a receptor binding assay, we characterized the pharmacology of a cloned neurokinin NK-2 receptor from human lung (hNK-2R), expressed in baculovirus-infected Sf-21 insect cells. Functional hNK-2R cDNA clones were isolated from human lung using a polymerase chain reaction-based(More)
Leukotrienes are naturally-occurring metabolites of arachidonic acid that are formed via the 5-lipoxygenase pathway in several tissues. Rat peritoneal cells (RPC) can produce leukotrienes C4, D4 and E4 (LTC4, LTD4 and LTE4) in response to stimulation with the calcium ionophore A23187 (1,2). The mechanism of enzymatic conversion of LTC4 to LTD4 is presumed(More)
The effects of peptidoleukotrienes (LTs) on electrically driven guinea pig left atria (GPLA) were investigated. LTD4 produced a positive inotropic response; however, rapid desensitization required the construction of noncumulative dose-response curves to naive tissues. The maximal inotropic response to LTD4 was 24 +/- 3% of isoproterenol and the EC50 = 267(More)
Fragment-based lead discovery has been successfully applied to the aspartyl protease enzyme beta-secretase (BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acid residues in the active site of the enzyme were the chemical starting points. Structure-based design approaches have led to identification of low(More)