Design, Synthesis, and Evolution of a Novel, Selective, and Orally Bioavailable Class of Thrombin Inhibitors: P1-Argininal Derivatives Incorporating P3-P4 Lactam …

…, DC Rowley, TK Brunck, T Ha-Uong…

Index: Semple; Rowley; Brunck; Ha-Uong; Minami; Owens; Tamura; Goldman; Siev; Ardecky; Carpenter; Ge; Richard; Nolan; Hakanson; Tulinsky; Nutt; Ripka Journal of Medicinal Chemistry, 1996 , vol. 39, # 23 p. 4531 - 4536

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Citation Number: 78

Abstract

Although CVS 1123 and other peptidyl argininals 10,11 have shown good thrombin inhibitory activity, oral bioavailability, and selectivity against related serine proteases including plasmin, coagulation factors VIIa (FVIIa) and Xa (FXa), they generally lack selectivity against trypsin. One strategy for achieving enhanced selectivity against trypsin was to focus on improving thrombin binding affinity by increasing conformational rigidity of the peptidic backbone ...