The X-ray crystal structures of four beta-strand-templated active site inhibitors of thrombin containing P1' groups have been determined and refined at about 2.1-A resolution to crystallographic R-values between 0.148 and 0.164. Two of the inhibitors have an alpha-ketoamide functionality at the scissile bond; the other two have a nonhydrolyzable electrophilic group at the P1' position. The binding of lysine is compared with that of arginine at the S1 specificity site, while that of D,L-phenylalanine enantiomorphs is compared in the S3 region of thrombin. Four different P1' moieties bind at the S1' subsite in three different ways. The binding constants vary between 2.0 microM and 70 pM. The bound structures are used to intercorrelate the various binding constants and also lead to insightful inferences concerning binding at the S1' site of thrombin.
Thrombin, a serine protease with trypsin-like specificity, plays a central role in the coagulation cascade by mediating both the final conversion of fibrinogen to fibrin and the activation of platelets. 1 The prominent anticoagulant therapeutic agents currently available, heparin and its low molecular weight derivatives, and the indirectly acting orally bioavailable coumarins suffer from many side effects and limited efficacy. 2 Considerable efforts to develop safer and novel thrombin inhibitors are presently underway. 3 Recently, in our laboratories, compound 1 (CVS 1123) was identified as a potent transition-state thrombin inhibitor which demonstrated good oral bioavailability and selectivity profiles (see Figure 1). 4 Molecularmodeling considerations and structure-activity relationship (SAR) studies on 1 and related serine protease inhibitors led to the design of compounds 2 (CVS 1578) and 3 (CVS 1778), 5 which incorporated a six-and a seven-membered lactam sulfonamide moiety at P 3 -P 4 , 6 respectively. The lactam template was based upon the pioneering work of Freidinger. 7 Both molecules displayed a high degree of selectivity for the inhibition of thrombin over trypsin (Table 1).
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