Novel small molecule bradykinin B1 receptor antagonists. Part 3: hydroxyurea derivatives.

Hydroxy urea moieties are introduced as a new class of bradykinin B(1) receptor antagonists. First, the SAR of the lead compound was systematically explored. Subsequent optimization resulted in the identification of several biaryl-based hydroxyurea bradykinin B(1) receptor antagonists with low-nanomolar activity and very high oral bioavailability in the rat.

Novel small molecule bradykinin B1 receptor antagonists. Part 1: benzamides and semicarbazides.

The synthesis and SAR of two series of bradykinin B(1) receptor antagonists is described. The benzamide moiety proved to be a suitable replacement for the aryl ester functionality of biaryl based antagonists. In addition, it was found that semicarbazides can effectively replace cyclopropyl amino acids. The compounds with the best overall profile were biaryl semicarbazides which display high antagonistic activity, low Caco-2 efflux and high oral bioavailability in the rat.

Novel small molecule bradykinin B1 receptor antagonists. Part 2: 5-membered diaminoheterocycles.

Efforts to find new bradykinin B(1) receptor antagonists identified 2-aminobenzimidazole as a novel core. Subsequent transformation into five-membered diaminoheterocycle derivatives and their synthesis and SAR is described. This resulted in compounds with low nanomolar activity.

Novel small molecule bradykinin B2 receptor antagonists.

Blockade of the bradykinin B(2) receptor provides therapeutic benefit in hereditary angioedema (HAE) and potentially in many other diseases. Herein, we describe the development of highly potent B(2) receptor antagonists with a molecular weight of approximately 500 g/mol. First, known quinoline-based B(2) receptor antagonists were stripped down to their shared core motif 53, which turned out to be the minimum pharmacophore. Targeted modifications of 53 resulted in the highly water-soluble lead compound 8a. Extensive exploration of its structure-activity relationship resulted in a series of highly potent B(2) receptor antagonists, featuring a hydrogen bond accepting functionality, which presumably interacts with the side chain of Asn-107 of the B(2) receptor. Optimization of the microsomal stability and cytochrome P450 inhibition eventually led to the discovery of the highly potent and orally available B(2) receptor antagonist 52e (JSM10292), which showed the best overall properties.

Sensitized photoinactivation of minigramicidin channels in bilayer lipid membranes.

The method of sensitized photoinactivation based on the photosensitized damage of gramicidin A (gA) molecules was applied here to study ionic channels formed by minigramicidin (the 11-residue analogue of gramicidin A) in a planar bilayer lipid membrane (BLM) of different thickness. Irradiation of BLM with a single flash of visible light in the presence of a photosensitizer (aluminum phthalocyanine or Rose Bengal) generating singlet oxygen provoked a decrease in the minigramicidin-induced electric current across BLM, the kinetics of which had the characteristic time of several seconds, as observed with gA. For gA, there is good correlation between the characteristic time of photoinactivation and the single-channel lifetime. In contrast to the covalent dimer of gA characterized by extremely long single-channel lifetime and the absence of current relaxation upon flash excitation, the covalent head-to-head dimer of minigramicidin displayed the flash-induced current decrease with the kinetics being strongly dependent on the membrane thickness. The current decrease became slower both upon increasing the concentration of the minigramicidin covalent dimer and upon including cholesterol in the membrane composition. These data in combination with the quadratic dependence of the current on the peptide concentration can be rationalized by hypothesizing that the macroscopic current across BLM measured at high concentrations of the peptide is provided by dimers of minigramicidin covalent dimers in the double beta(5.7)-helical conformation having the lifetime of about 0.4 s, while single channels with the lifetime of 0.01 s, observed at a very low peptide concentration, correspond to the single-stranded beta(6.3)-helical conformation. Alternatively the results can be explained by clustering of channels at high concentrations of the minigramicidin covalent dimer.

Mobility of a one-dimensional confined file of water molecules as a function of file length.

Confinement of water by pore geometry to a one-dimensional file of molecules interacting with the pore alters the diffusion coefficient D(W). Here we report an exponential dependence of D(W) on the number of water positions in the pore. The result is based on measurements of single channel water permeabilities of structurally similar peptidic nanopores of different length. The inconsistency with predictions from continuum or kinetic models indicates that pore occupancy is reduced in single file transport. In longer pores (e.g., in aquaporins) the presence of charged residues increases D(W).