Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 160

Another cyclic peptide specific for a IIb b 3 is already successfully sold by
Schering-Plough under the name Integrilin as prevention for myocardial
infarction (turnover: 325 million USD in 2004). The heptapeptide
cyclo-S,S -[Mpa-Har-Gly-Asp-Trp-Pro-Cys]-NH 2 behind the marketing
name is called eptifibatide and contains two-non-natural building blocks 3-
mercaptopropanoic acid (Mpa) and homoarginine (Har). (Figure 4.15).
Figure 4.15 Eptifibatide, an a IIb b 3 antagonist marketed under the name Integrilin,
and two peptides with more constrained disulfide bonds and better affinities. All IC 50
values are given for the inhibition of binding of integrin a IIb b 3 to fibronectin
Eptifibatide is an analogue of the highly specific a IIb b 3 disintegrin
barbourin, which originally contained a lysine instead of the arginine in
the RGD motif. Here, cyclic disulfide-bridged templates were success-
fully chosen to optimize affinity and bioavailability [145-148].
Along with other modifications like N-methylation and reduction of
the ring size, the flexible disulfide bridge was rigidified by incorporation
of penicillamine (Pen) instead of cysteine. This led to the peptide
Ac-cyclo -S,S -[Cys-(NMe)Arg-Gly-Asp-Pen]-NH 2 and an increase in affi-
nity over 100-fold better than eptifibatide. Subsequent derivatization in
the direction of semipeptides led to the replacement of the disulfide tether
with 2-mercaptobenzoyl/2-mercaptoaniline (Mba/Man), constraining
the w torsion angle to 0, which led to significant enhancement of affinity
and potency [149].