RGD mimetics

The hydantoin moiety has been utilized as a biostere for the peptide linkage, transforming a peptide lead into an orally available drug candidate. Therefore, an Arg-Gly-Asp-Ser tetrapeptide (18) lead structure was modified to a non-peptide RGD mimetic as an orally active fibrinogen receptor antagonist 19. ° ... 

Fig. 3. Conformational states for integrins. A-C. Model for a l3 integrin activation, with at least three conformations of the extracellular domain (Takagi et al, 2002). (A) Bent, low affinity conformation. (B) Extended conformation with closed headpiece. (C) Extended conformation with open headpiece shown with bound RGD-mimetic peptide (green CPK). D-H. Model for aiJ3 integrin activation. (D) Bent conformation with low affinity. (E) and (F) with a closed headpiece and closed I domain in...

Peptides containing the RGD sequence can also be used in cancer diagnostics due to then-ability of interacting with integrins that are responsible parts for platelet adhesion, activation, and leukocyte mobility and for cancer cell dissemination. As a consequence, RGD peptides and RGD mimetics bind to cancer cells and can be used for diagnosis (Sivolapenko et al. 1998). 

In instanees where a functionalized aromatic moiely is desired in the target structure, the Heck reaction of an atyl/vinyl halide/triflate with an alkene in the presenee of a palladium catalyst and base is an obvious choice and, indeed, has found application in the macrocycle arena. The first demonstration of a Pd(0) process on the solid phase actually involved Heck chemistry and was directed toward the synthesis of small libraries containing 20- to 24-membered macrocycles (94, Scheme 11.10). Analogous procedures were employed for the assembly of macrocyclic RGD mimet-ics °° and p-turn mimics (97, Figure 11.12, site of reaction and palladium species employed indicated) on the solid phase. For these conversions, it was postulated that an intramolecular hydrogen bond in the precursor assisted in the formation of the cycle. 

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