Peptidomimetics conformationally restricted

The multiple conformational restriction of dermorphin-related tet-rapeptide analogues that was performed represents a rational design of opioid peptidomimetics characterized by a high degree of structural rigid-ification. This is indicated by the fact that the p-selective agonist H-Hat-D-Orn-Aic-Glu-NH2 contains only two freely rotatable bonds, whereas there are 14 freely rotatable bonds in [Leu5]enkephalin. 

Riva and coworkers obtained conformationally restricted cyclic peptidomimetics 13a and b by a tandem Ugi-4CR/RCM procedure as reported before (Scheme 13). The initial A-alkylated dipeptide moiety was formed in the Ugi reaction of A-Boc... 

As in the case of the five-membered proline analogues, besides pipecolic acid (6) as the six-membered homologue of proline, related aza-, oxa-, and thia-analogues are used to mimic the conformationally restricting properties of proline in the peptidomimetic design of bioactive compounds.1202 ... 

Recently, much attention has been directed toward the synthesis of peptidomimetics. These compounds can replace native peptides in the interaction with receptors. They showed increased metabolic stability, better bioavailability, and longer duration of action than native peptides, thus displaying favorable pharmacological properties [52-54]. In this sense, the design and synthesis of conformationally restricted peptidomimetics is an important approach toward improving the potency, selectivity, and metabolic stability of peptide based chugs. 

The introduction of conformational restrictions into flexible active molecules is a well-known strategy for trying to increase their potency and/or selectivity toward their biological targets.1 Several methods have been used for constraining flexible molecules. Cyclic derivatives of hnear peptides or peptidomimetics can thus be prepared by reactions involving side-chain... 

Liskamp RMJ. Conformationally restricted amino acid and dipeptides, (non)peptidomimetics and secondary structure mimetics. Rec. Trav. Chim. Pays-Bas 1994 113 1-19. 

An outstanding example in peptidomimetic design evolved from these studies. Truncation and conformational restriction of a reduced isostere of the parent peptide substrate, followed by systematic replacement of the peptide-like side-chains provided the potent non-peptidic inhibitor (111)(Fig. 15.46) (207). This approach highlights the transition from a peptide-derived structure to a compound with no apparent resemblance to the original peptide. 

R. M. J. Liskamp, Reel. Trav. Chim. Pays-Bas, 113, 1 (1994). Conformationally Restricted Amino Acids and Dipeptides (Non)Peptidomimetics and Secondary Structure Mimetics. 

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