Protease inhibitors. Part 2. Weakly basic thrombin inhibitors incorporating sulfonyl-aminoguanidine moieties as S1 anchoring groups: Synthesis and structure-activity correlations

Two series of derivatives have been prepared and assayed as inhibitors of t wo physiologically relevant serine proteases, human thrombin and human tryp sin. The first series includes alkyl-/aralkyl-/aryl- and hetarylsulfonyl-am inoguanidines. It was thus observed that sulfanilyl-aminoguanidine possesse s moderate but intrinsically selective thrombin inhibitory properties. with K-I values around 90 and 1400 nM against thrombin and trypsin respectively . Further elaboration of this molecule afforded compounds that inhibited th rombin with K-I values in the range 10-50 nM, whereas affinity for trypsin remained relatively low. Such compounds were obtained either by attaching b enzyloxycarbonyl- or 4-toluenesulfonylureido-protected amino acids (such as D-Phe, L-Pro) or dipeptides (such as Phe-Pro, Gly-His, beta-Ala-His or Pro -Gly) to the N-4 atom of the lead molecule. sulfanilyl-aminoguanidine, or b y attaching substituted-pyridinium-propylcarboxamido moieties to this lead. Thus, this study brings novel insights regarding a novel non-basic S1 anch oring moiety (i.e., SO2NHNHC(=NH)NH2). and new types of peptidomimetic scaf folds obtained by incorporating tosylureido-amino acids/pyridinium-substitu ted-GABA moieties in the hydrophobic binding site(s). Structure-activity co rrelations of the new serine protease inhibitors are also discussed based o n a QSAR model described previously for a large series of structurally-rela ted derivatives (Supuran et al. (1999) J. Med. Chem., in press).