title: Synthesis and biological activity of ketomethylene pseudopeptide analogues as thrombin inhibitors.
abstract: Ketomethylene pseudopeptide analogues Aa-Pro-Arg psi (COCH2) Gly-pip, 1, where Aa are D- or L-amino acids (Dpa, beta, beta-diphenylalanine; alpha Nal, alpha-naphthylalanine; beta Nal, beta-naphthylalanine; Fgl, fluorenylglycine) with highly lipophilic side chains and psi (COCH2) is a ketomethylene pseudopeptide bond, have been synthesized through a modified Dakin-West reaction under very mild conditions with a high yield using tripeptide 4 with a labile functional group directly on the side chain. Their enzymatic assay of thrombin inhibition has been carried out. The structure-activity relationship study indicated that a lipophilic side chain on the amino acid in the P3 position is very important for binding to the apolar site of thrombin. Compound 1a with D-Dpa at the P3 position has a Ki of 0.2 microM and it doubles thrombin clotting time at only 3 times higher concentration. These values are about 7 times better than those of the corresponding D-Phe analogues. Furthermore, 1a shows poor inhibitory activity against plasmin, factor Xa, urokinase, and kallikrein. Preliminary in vivo testing (3-4-kg rabbit as the animal model) shows no observable side effect (change of blood pressure and accumulation of blood platelet in lungs) at a dose of 1 mg/kg.
authors.affiliation: Thrombosis Research Institute, London, U.K.
authors.forename: L
authors.initials: L
authors.lastname: Cheng
authors.forename: C A
authors.initials: CA
authors.lastname: Goodwin
authors.forename: M F
authors.initials: MF
authors.lastname: Schully
authors.forename: V V
authors.initials: VV
authors.lastname: Kakkar
authors.forename: G
authors.initials: G
authors.lastname: Claeson
mesh_terms: D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D010455:Peptides; D013917:Thrombin