Previously we reported the discovery of amidothiophenesulfonamides as endothelin receptor-A antagonists with high potency and selectivity. Replacement of an amide group in this class of compounds with an acetyl group maintained the in vitro binding affinity and in vivo activity while providing a compound with oral bioavailability and longer duration of action. The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ETA receptors with a Ki of 0.43 +/- 0.03 nM and an IC50 of 1.4 nM (IC50 for ETB = 9800 nM). This compound inhibits ET-1-induced stimulation of phosphoinositide turnover with a Ki of 0.686 nM and a pA2 of 8.0. The compound has a serum half-life in the rat and the dog of 6-7 h and 60-100% oral bioavailability. This compound is one of the most selective ETA antagonists reported and therefore is suitable for additional pharmacological and clinical investigation of the role of ETA receptors in diseases.

Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. ␤-Lactamase overexpression is a common mechanism of bacterial resistance to ␤-lactam antibiotics. We present here the results for one of the ␤-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold. Unlike conventional ␤-lactam antibiotics, where hydrolysis of the ␤-lactam ring inactivates the antibiotic, hydrolysis of NB2001 by ␤-lactamase releases triclosan. Evidence supporting the proposed mechanism is as follows. (i) NB2001 is a substrate for TEM-1 ␤-lactamase, forming triclosan with a second-order rate constant (k cat /K m ) of greater than 77,000 M ؊1 s ؊1 .(ii) Triclosan is detected in NB2001-treated, ␤-lactamase-producing Escherichia coli but not in E. coli that does not express ␤-lactamase. (iii) NB2001 activity against ␤-lactamaseproducing E. coli is decreased in the presence of the ␤-lactamase inhibitor clavulanic acid. NB2001 was similar to or more potent than reference antibiotics against clinical isolates of Staphylococcus aureus (including MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Moraxella catarrhalis and Haemophilus influenzae. NB2001 is also active against Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. The results indicate that NB2001 is a potent, broad-spectrum antibacterial agent and demonstrate the potential of ECTA in overcoming ␤-lactamase-mediated resistance.

uprostenol. In the rat uterus, PGF 2a 1-OH was about two orders of magnitude less potent than 17-phenyl PGF 2a whereas PGF 2a 1-OCH 3 produced only a minimal e ect. 4 Radioligand binding studies on cat lung parenchymal plasma membrane preparations suggested that the cat lung parenchyma does not contain a homogeneous population of receptors that equally respond to PGF 2a 1-OH, PGF 2a 1-OCH 3 , and classical FP receptor agonists. 5 Studies on smooth muscle preparations and cells containing DP, EP 1 , EP 2 , EP 3 , EP 4 , IP, and TP receptors indicated that the activity of PGF 2a 1-OH and PGF 2a 1-OCH 3 could not be ascribed to interaction with these receptors. 6 The potent e ects of PGF 2a 1-OH and PGF 2a 1-OCH 3 on the cat lung parenchyma are di cult to describe in terms of interaction with the FP or any other known prostanoid receptor.

We report here that N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides are potent and selective small molecule ETA receptor antagonists. The aryl group was subjected to extensive structural modification. With monosubstitution, the para position was most useful in increasing potency, with methyl being preferred. With disubstitution, 2,4-disubstitution further enhanced activity with methyl or cyano groups being preferred at the 2-position. In this series, a benzo-[d][1,3]dioxole group is equivalent to a 4-methyl group in in vitro activity and afforded the compounds with both in vivo activity and moderate half-lives.

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