No abstract

A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein−protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC 50 of 0.44 μM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.

Synthesis and characterization of poly(quinoxaline vinylene)s and poly(pyridopyrazine vinylene)s with linear and branched aliphatic side chains are reported. The electron affinity of the polymers was measured with cyclic voltammetry (CV) and found to be highest for the pyridopyrazine vinylene polymers. Compared to CN-MEH-PPV, the pyridopyrazine vinylene polymers were easier to reduce, while the quinoxaline derivatives were harder. UV-vis absorption measurements showed that the polymers have relatively small band gaps.

The synthesis and characterization of poly(pyridine vinylene) (PPyV) via the nonionic sulfinyl precursor route is presented. Starting from an unsymmetrical monomer, precursor polymers were prepared in various solvents, which led to polymers with variable molecular weights. The thermal conversion to the conjugated structure, as well as its stability, was studied with different techniques such as FT-IR, UV-vis, TGA, and direct insertion probe mass spectroscopy (DIP-MS). From these results we were able to derive the most suitable conditions to perform the conversion. The fully conjugated PPyV was further characterized with photoluminescence (PL) and cyclic voltammetry (CV) measurements. The PL efficiency was found to be as high as 14%. The CV measurements showed that the polymer can be reduced (ndoped).