The discovery of orally available thrombin inhibitors: Optimisation of the P1 pharmacophore

More than a Simple Lipophilic Contact: A Detailed Thermodynamic Analysis of Nonbasic Residues in the S1 Pocket of Thrombin

“…3 Ongoing efforts to produce therapeutically useful orally available thrombin inhibitors resulted in the discovery of the uncharged m-chloro-benzylamides as promising alternatives to the prodrug strategy. 4 They are assumed to form a lipophilic contact in the S1 pocket, [5][6][7][8] which has the polar carboxylate group of Asp189 at its far end. Therefore the rationalization put forward [5][6][7][8] to explain the pronounced binding affinities of the m-chloro derivatives as predominantly hydrophobic binding appears unsatisfactory.…”

SNAr or Sulfonylation? Chemoselective Amination of Halo(het)arene Sulfonyl Halides for Synthetic Applications and Ultralarge Compound Library Design

“…We have aimed to classify these compounds according to the relative reactivity of both electrophilic centers toward amination and hence the possibility of their application in one- and two-step parallel synthesis. Obviously, there are many literature precedents of chemoselective modification of compounds 7 in the reactions with amines, − but to the best of our knowledge, no systematic studies in this area have been performed. Furthermore, we demonstrate application of these building blocks for the generation of ultralarge readily accessible (“REAL”) chemical space and illustrate its tractability by preparation of a nearly 700-member compound library.…”