Inhibitors and substrates of thrombin

A peptide of the formula:

• wherein
• (I) X is:
• H, CH3 or an N-protecting group;
• (II) Y is:
• (1) (CH2)n—Q or
• wherein Q is H, amino, amidino, imidazole, guanidino or isothioureido and n is 1-5,
• (2) nitrophenyl, cyanophenyl, aminophenyl, pyridyl or the side chain of His, or
• (3) C3-C9 alkyl, C5-C10 aryl or C5-C10 alkylaryl optionally substituted by up to three groups selected from hydroxy and C1-C4 alkoxy;
• (III) Z is:
• CN, COR1,
• wherein
• (1) R1 is H, OH, CH2Cl, CH2—CH2—CO-pip, CF2—CF2—CO-pip, CH2—CH(CH3)—CO-pip, CF2—CF(CF3)—CO-pip, CH2—CH2—CO-Pro-NHEt, CF2—CF2—CO-Pro-NHEt or a chromophoric group,
• (2) R2 and R3 are the same or different and are selected from the group consisting of OH, OR6 and NR6R7 wherein R6 and R7 are the same or different and are C1-C10 alkyl, phenyl or C6-C10 arylalkyl, or R2 and R3 taken together represent the residue of a diol, and
• (3) R4 and R5 are the same or different and are selected from R2 and R3 as recited above, Gly-pip, Ala-pip or Gly-Pro-NHEt;
• (IV) Aa1 is:
• wherein:
• (1) Ar1 and Ar2 are the same or different and are selected from the group consisting of:
• phenyl, thienyl, pyridyl, naphthyl, thionaphthyl, indolyl and saturated groups corresponding to these, optionally substituted by up to three groups selected from C1-C3 alkyl and C1-C3 alkoxy,
• (2) L1 and L2 are the same or different and are selected from the group consisting of CH2, CH2—CH2, O—CH2, and S—CH2
• or
• (3) Ar1—L1 or Ar2—L2 taken together are H, diphenylmethyl, fluorenyl or saturated groups corresponding to these;
• except that when Aa1 is phenylalanine or glycine, then Y is not:
• (a) (CH2)3—NH—C(NH2)2,
• (b) C3-C9 alkyl optionally substituted by C1-C4 alkoxy or
• (c)
• and
• (V) Aa2 is
• or its C1-C3 alkyl substituted derivatives, where R8 is CH2, CH2—CH2, S—CH2, S—C(CH3)2 or CH2—CH2—CH2.