Nonpeptide mimetics

Structure Antibody Fab fragment Nonpeptide mimetic Cyclic heptapeptide... 

Eptifibatide is a cyclic heptapeptide based upon the Lys-Gly-Asp sequence. Tirofiban and lamifiban are nonpeptide mimetics. All three are competitive inhibitors of the GPIIb-IIIa complex with lower affinities and higher dissociation rates than abciximab and short plasma t/ (2-2.5 h). Platelet aggregation returns to normal 30 min to 4 h after discontinuation. Eptifibatide and tirofiban are effective in acute coronary syndromes. Lamifiban is xmdergoing clinical development. 

Table 2.17 Nonpeptide Mimetics for Delta Opioid Receptors Based on Delta Opioid Peptides...

M. Kahn and S. Wilke, Peptide Chem., Struct. Biol., Proc. 11th Am. Peptide Symp., 489 (1990). The Design and Synthesis of Nonpeptide Mimetics of Erabutoxin B. 

S3mthetic nonpeptide mimetics of a-helices (terp5uidines, 1,4-benzodiaze-pin-2,5-dione, polycyclic ethers, trisubstituted imidazoles as mimetics) 07CSR326. 

In the late 1980s when we began the pursuit of bradykinin receptor antagonists, information of relevance to medicinal chemists was scarce. For example, not one nonpeptide antagonist of this receptor was known, nor were any series upon which to base a structure-activity relationship. Moreover, all publications described bradykinin as being highly flexible in an aqueous environment, such that no structural mimetics could be rationalized. Of course the receptors had not been cloned at that time so nothing was known about the primary sequence of the receptor or the three-dimensional structure. 

The same group has also reported the synthesis of the nonpeptide enkephalin (3-tum mimetic 216 [162]. The key step of the approach, Scheme 64, involves the simultaneous intramolecular cyclization/(3-lactam ring cleavage in derivative 215 leading to compound 216. 

Another protein A mimetic molecule of nonpeptide nature was recently described.203 The nature of the ligand was not disclosed but was described as able to bind a large variety of immunoglobulin G and M from different animal species. In typical experiments the capacity described was in the range of 1.2 to 11.5 mg per milliliter of resin purity of immunoglobulins was in the range of 35 to 99% and the recovery of 90-98%. 

Hniby et al. used their bioactive conformation model for [(2S,3J2)TMT ]DPDPE for a different purpose (Fig. 2.9), that is, to design nonpeptide peptide mimetics. A major interest of medicinal chemists is the development of peptide mimetics (235). The concept of pep-... 

Figure 2.9. Conversion of (2jS,3i2)TMT -c[DPDPE] into a nonpeptide peptide mimetic based on topographical considerations.

In order to improve cellular permeabihty nonpeptidic pTyr mimetics have been designed and compound 179 was found as a potent, cell permeable inhibitor of PTPIB [57]. 

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