Inhibitors and substrates of thrombin

Abstract

Peptides which act as inhibitors or substrates of thrombin are derived from the formula: D-Phe-Pro-Arg or its analogues, wherein Phe is substituted by (a), wherein Ar.sub.1 or Ar.sub.2 are the same or different and are selected from the group consisting of phenyl, thienyl, pyridyl, naphthyl, thionaphtyl, indolyl and saturated groups corresponding to these, optionally substituted by up to three groups selected from C.sub.1 -C.sub.3 alkyl and C.sub.1 -C.sub.3 alkoxy, L.sub.1 and L.sub.2 are the same of different and are selected from the group consisting of CH.sub.2, C.sub.2 --C.sub.2, O-CH.sub.2, S-CH.sub.2, Ar-L taken together optionally means H, diphenyl-methyl, fluorenyl or saturated groups corresponding to these, but one of the Ar-L cannot be H when the other [CH.sub.2 ].sub.n -Q, (c) where Q=H, amino, amidino, imidazole, guanidino or isothioureido and n=1-5, preferably 3-5, or C.sub.3 -C.sub.9 alkyl and C.sub.5 -C.sub.10 aryl or alkylaryl optionally substituted by up to three groups selected from hydroxy and C.sub.1 -C.sub.4 alkoxy; Z=CN, COR.sub.1, (d) or (e), where R.sub.1 =H, OH, CH.sub.2 Cl, CH.sub.2 --C.sub.2 --CO--pip, CF.sub.2 --CF.sub.2 --CO--pip, (f), (g), CH.sub.2 --C.sub.2 --CO--Pro--NHEt, CF.sub.2 --CF.sub.2 --CO--Pro--NHEt or a chromophoric group e.g. pHA, MCA, R.sub.2 and R.sub.3 are the same or different and are selected from the group consisting of OH, OR.sub.6 and NR.sub.6 R.sub.7, or R.sub.2 and R.sub.3 taken together represent the residue of a diol; where R.sub.6 and R.sub.7, which are the same or different, are C.sub.1 -C.sub.10 alkyl, phenyl or C.sub.6 -C.sub.10 arylalkyl, R.sub.4 and R.sub.5 are the same or different and are selected from R.sub.2, R.sub.3, Gly-pip, Ala-pip or Gly-Pro-NHEt.