Guanylpiperidine peptidomimetics: potent and selective bis-cation inhibitors of factor Xa

A novel series of rigid P3-guanylpiperidine peptide mimics Figure 1 and Scheme 1 was designed as potential factor Xa and prothrombinase inhibitors. Incorporation into a P2-gly-P1-argininal motif led to highly potent and selective inhibitors. The synthesis and biological activities of these derivatives are reported herein. Figure 1. Strategy for the design of guanylpiperidine inhibitors 3–14. Scheme 1. Reagents and conditions: (a) H2, PtO2, EtOH, AcOH, H2O, quant; (b) MeSC(NCbz)(NHCbz), DIEA, THF, Δ, 41%; (c) H-Gly-OEt, HCl salt, EDC, HOBt, DIEA, CH3CN, 53%; (d) HCl, EtOH; (e) BnSO2Cl, NMM, CH3CN, 16–26% for two steps; (f) 1.0 N LiOH, EtOH; (g) EDC, HOBt, nitroargininal ethyl aminal•HCl, NMM, CH3CN, 43–88% for two steps; (h) H2, 10% Pd/C, EtOH, H2O, HOAc; (i) 6.0 N HCl; preparative RP HPLC, 14% for 3a, 24% for 3b.