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.

Crystal engineering on industrial diaryl pigments using lattice energy minimizations and X-ray powder diffraction.

Diaryl azo pigments play an important role as yellow pigments for printing inks, with an annual pigment production of more than 50,000 t. The crystal structures of Pigment Yellow 12 (PY12), Pigment Yellow 13 (PY13), Pigment Yellow 14 (PY14), and Pigment Yellow 83 (PY83) were determined from X-ray powder data using lattice energy minimizations and subsequent Rietveld refinements. Details of the lattice energy minimization procedure and of the development of a torsion potential for the biphenyl fragment are given. The Rietveld refinements were carried out using rigid bodies, or constraints. It was also possible to refine all atomic positions individually without any constraint or restraint, even for PY12 having 44 independent non-hydrogen atoms per asymmetric unit. For PY14 (23 independent non-hydrogen atoms), additionally all atomic isotropic temperature factors could be refined individually. PY12 crystallized in a herringbone arrangement with twisted biaryl fragments. PY13 and PY14 formed a layer structure of planar molecules. PY83 showed a herringbone structure with planar molecules. According to quantum mechanical calculations, the twisting of the biaryl fragment results in a lower color strength of the pigments, whereas changes in the substitution pattern have almost no influence on the color strength of a single molecule. Hence, the experimentally observed lower color strength of PY12 in comparison with that of PY13 and PY83 can be explained as a pure packing effect. Further lattice energy calculations explained that the four investigated pigments crystallize in three different structures because these structures are the energetically most favorable ones for each compound. For example, for PY13, PY14, or PY83, a PY12-analogous crystal structure would lead to considerably poorer lattice energies and lower densities. In contrast, lattice energy calculations revealed that PY12 could adopt a PY13-type structure with only slightly poorer energy. This structure was found experimentally as a metastable gamma phase of PY12. Calculations on mixed crystals (solid solutions) showed that mixed crystals of PY12 and PY13 should adopt the PY13 structure with planar molecules, resulting in high color strengths; this was proven experimentally (Pigment Yellow 188). Similarly, the high color strength of mixed crystals consisting of PY13 and PY14 (Pigment Yellow 174), and PY13/PY83 (Pigment Yellow 176) is explained by the crystal structures.

Design and synthesis of a new class of selective integrin alpha5beta1 antagonists.

Starting from the structure of integrin alphavbeta3 in a complex with a peptidic ligand plus SAR data on nonpeptidic ligands, we derived a new class of integrin alpha5beta1 antagonists (1). Several synthesis strategies were applied to evaluate the chemical space around the essential pharmacophore groups R1 to R3 to obtain highly active and selective pyrrolidine derivatives as integrin alpha5beta1 antagonists. Integrin selectivity was controlled by switching from a sulfonamide moiety to a mesitylene amide moiety for R3. This finding represents a general feature for modulating selectivity toward other related integrin receptors. On the basis of the encouraging results from various in vitro studies, the most active compounds were selected for further in vivo studies in animal models and preclinical development.