title: Protease inhibitors - Part 3. Synthesis of non-basic thrombin inhibitors incorporating pyridinium-sulfanilylguanidine moieties at the P1 site.
abstract: Using benzamidine and sulfaguanidine as lead molecules, three series of derivatives have been prepared by reaction of sulfaguanidine with pyrylium salts, with the pyridinium derivatives of glycine and with the pyridinium derivatives of beta-alanine, respectively. The new compounds were assayed as inhibitors of two serine proteases, thrombin and trypsin. The study showed that in contrast to the leads, possessing K(I)'s around 100-300 nM against thrombin, and 1200-1500 nM against trypsin, respectively, the new derivatives showed inhibition constants in the range of 15-50 nM against thrombin, whereas their affinity for trypsin remained relatively low. Derivatives of beta-alanine were more active than the corresponding Gly derivatives, which in turn were more inhibitory than the pyridinium derivatives of sulfaguanidine possessing the same substitution pattern at the pyridinium ring. Thus, the present study proposes two novel approaches for the preparation of high affinity, specific thrombin inhibitors: a novel S1 anchoring moiety in the already large family of arginine/amidine-based inhibitors, i.e., the SO(2)N=C(NH(2))(2) group, and novel non-peptidomimetic scaffolds obtained by incorporating alkyl-/aryl-substituted-pyridinium moieties in the hydrophobic binding site(s). The first one is important for obtaining bioavailable thrombin inhibitors, devoid of the high basicity of the commonly used arginine/amidine-based inhibitors, whereas the second one may lead to improved water solubility of such compounds due to facilitated salt formation as well as increased stability at hydrolysis (in vivo).
authors.affiliation: Università degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Via Gino Capponi 7, I-50121, Florence, Italy
authors.initials: A
authors.lastname: Scozzafava
authors.initials: F
authors.lastname: Briganti
authors.initials: CT
authors.lastname: Supuran