DERIVATIVES OF 4-AMINO-PYRIDINE AS SELECTIVE THROMBIN INHIBITORS

During screening for novel thrombin inhibitors it was discovered that the il-aminopyridine derivative 1 inhibits human alpha-thrombin compet itively and selectively. The 4-aminopyridine moiety itself is most lik ely the major determinant of the selectivity due to the increased hydr ophobicity of the S1 pocket in thrombin compared to trypsin and plasmi n. Optimization led to the selective thrombin inhibitor 14 with an inh ibition constant, Ki of 70 nM. (C) 1997 Elsevier Science Ltd.