Wolfgang von der Saal

Phthalazinone Pyrazoles as Potent, Selective, and Orally Bioavailable Inhibitors of Aurora-A Kinase

The inhibition of Aurora kinases in order to arrest mitosis and subsequently inhibit tumor growth via apoptosis of proliferating cells has generated significant discussion within the literature. We report a novel class of Aurora kinase inhibitors based upon a phthalazinone pyrazole scaffold. The development of the phthalazinone template resulted in a potent Aurora-A selective series of compounds (typically >1000-fold selectivity over Aurora-B) that display good pharmacological profiles with significantly improved oral bioavailability compared to the well studied Aurora inhibitor VX-680.

DERIVATIVES OF 4-AMINO-PYRIDINE AS SELECTIVE THROMBIN INHIBITORS

Abstract During screening for novel thrombin inhibitors it was discovered that the 4-aminopyridine derivative 1 inhibits human α-thrombin competitively and selectively. The 4-aminopyridine moiety itself is most likely the major determinant of the selectivity due to the increased hydrophobicity of the S1 pocket in thrombin compared to trypsin and plasmin. Optimization led to the selective thrombin inhibitor 14 with an inhibition constant, Ki of 70 nM.

Diarylsulfonamides as selective, non-peptidic thrombin inhibitors

Based on the structures of aminopyridine thrombin inhibitors (1), a series of aminoalkyl- and guanidinoalkyl-substituted diarylsulfonamides were prepared. The most potent derivative, N-[3-(4-guanidinobutoxy)-5-methyl-phenyl]-benzenesulfonamide (6c) had Ki = 0.18 microM for thrombin and did not inhibit trypsin, plasmin, or factor Xa. Comparison of the X-ray structures of the thrombin/1b and the thrombin/6c complexes revealed important aspects which govern the binding of such diarylsulfonamides to thrombin.

Improved Procedures For Large Scale Preparation Of 6- and 7-Oxy-Substituted Isoquinolines and A Convenient Work-Up Protocol For Titanium Supported Reactions

Abstract Improved procedures for large scale preparation of oxy-substituted isoquinoiines are reported. Moreover, a simple and convenient protocol for alkaline work-up of titanium containing reaction mixtures is given, which is expected to be of general interest even for reactions on a technical scale.