Active site-directed thrombin inhibitors: α-hydroxyacylprolyl-arginals. New orally active stable analogs of d-Phe-Pro-Arg-H

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Abstract

d-α-Hydroxyacyl-prolyl-arginals have been designed and synthesized as orally active stable analogs of d-Phe-Pro-Arg-H, the active site-directed peptidyl thrombin inhibitor prototype. Many of the new analogs possess high in vitro anticoagulant activity while having little effect on fibrinolysis. Compounds GYKI-66104 (2), −66131 (3) and −66132 (5) effectively delay the clotting time in rabbits ex vivo and prevent thrombus formation in various thrombosis models in rabbits and rats when applied in a single oral dose of 5 mg kg−1

Synthesis and evaluation of title compounds are described. Some analogues (e.g. 2) are potent anticoagulants in vitro and show significant oral activities in adose of 5 mg/kg, i.e. delay clotting times and inhibit thrombus formation.

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    Hac = Man (1), Hpl (3), Pla (4), or Hma (5). Reagents; i, MeOH/0.05 equiv. H2SO4; ii, 1 equiv. dihydropyran/0.05 equiv. HCl/EtOAc in CH2Cl2; iii, NaOH/MeOH; iv, HOTcp/DCC in THF; v, coupling in DMF/l equiv. NEt3; vi, mixed anhydride coupling; vii, LiAlH4/THF; viii, H2/Pd in EtOH/0.5 M H2SO4 (1 equiv.); ix, catalyst removed, pH adjusted to 3.6, kept at 20 °C for 24 h.

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