[Macroporous polyacrylamide, its use for immunological diffusion techniques].

Four types of ion-selective channels were found by the patch-clamp technique in the human erythroleukemia K562 cells. I) in cell-attached configuration at potentials less negative than -40 mV an 8 ps channel was detected. The potential dependence of channel activity suggests that this is the TTX-sensitive Na+ channel. II) A cation-selective channel was observed with equal permeability for Na+ and K+ and a potential-independent single-channel conductance of 19 pS. The channel is activated by intracellular Ca2+ and inhibited by TEA, III) A predominantly anion-selective channel was identified with the selectivity sequence NO3- > J- > Cl- = Br- >> SO4(2-). The single-channel conductance shows outward rectification, and is in symmetrical NaCl solution 19 pS at -60 mV and 54pS at +50 mV. The open- and closed-time distributions suggest one open and at least four closed states. At submicromolar concentrations, the open state is blocked by H2DIDS leading to channel flicker between open and blocked channel; higher concentrations (apparent KI = 6.8 uM) lead to a longer-lasting blocked state. Both components of inhibition are reversible. IV) In addition, an 8 pS, Na(+)- and K(+)- selective channel could be induced by application of palytoxin. For channel activity, the presence of extracellular Na+ is essential. It is assumed that the Na+, K(+)-pump molecule is involved in the channel formation. Similarly, it is discussed whether the anion-selective channel represents a pore conformation of an electrically silent anion exchanger.

Acrylamides↗

PubMed2002

Substituted acrylamides as factor Xa inhibitors: improving bioavailability by P1 modification.

To overcome the low bioavailability of our substituted acrylamide P1 benzamidine factor Xa inhibitors reported previously, neutral and less basic groups were used to replace the benzamidine. As a result, a series of P1 aminoisoquinoline substituted acrylamide Xa inhibitors was identified to be potent, selective, and orally bioavailable. Modification of P4 moiety of these compounds further improved their pharmacokinetic properties.

Acrylamides↗

PubMed2002

Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI).

Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.

Acrylamides↗