Protease inhibitors: Synthesis and QSAR study of novel classes of nonbasicthrombin inhibitors incorporating sulfonylguanidine and O-methylsulfonylisourea moieties at p1

Using benzamidine as a lead molecule, two series of alkyl/aralkyl/arylsulfo nylguanidines/sulfonyl-O-methylisoureas have been prepared and assayed as i nhibitors of two serine proteases, thrombin and trypsin. The study showed t hat sulfaguanidine and its corresponding O-methylisourea derivative possess moderate but intrinsically selective thrombin inhibitory properties, with K-I's around 100 nM against thrombin and 1350-1500 nM against trypsin. Furt her elaboration of these two molecules afforded compounds that inhibited th rombin with KI's in the range of 12-50 nM, whereas affinity for trypsin rem ained relatively low. Such compounds were obtained by attaching benzyloxyca rbonyl- or 4-toluenesulfonylureido-protected amino acids (such as L- and D- Phe or L-Pro) or dipeptides (such as Phe-Pro, Gly-His, P-Ala-His, or Pro-Gl y) to the two leads mentioned above, sulfaguanidine and 4-aminobenzenesulfo nyl-O-methylisourea. Thus, the present study proposes two novel approaches for the preparation of high-affinity, specific thrombin inhibitors: two nov el S1 anchoring moieties in the already large family of arginine/amidine-ba sed inhibitors and novel peptidomimetic scaffolds obtained by incorporating tosylureido amino acids 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, where as the second one may lead to improved water solubility of such compounds d ue to facilitated metal (sodium) salts formation (at the relatively acidic SO2NHCO protons) as well as increased stability at hydrolysis (in vivo). A QSAR study also explained the activity in terms of global properties of the molecules, electronic properties of the sulfonylguanidine/sulfonylisourea moiety, and novel descriptors, the frontier orbital phase angles (FOPA), th at account for the directions of the nodes in the pi orbitals in the aromat ic portion of those of the drugs in which the sulfonyl group was bound to a benzene ring. For thrombin inhibition, the size of the molecule was the do minant influence, while for trypsin inhibition the FOPA was the principal d eterminant of activity. The dependence of activity on the FOPA variables is perhaps the dearest example of a quantum effect in pharmacology and sugges ts a promising new tool for drug design.