Novel Conformationally Restricted Amino Acids for Peptidomimetic Drug Design

Conformationally restricted amino acids and peptides in which conformational freedom is substantially reduced by the presence of small rings have obtained a prominent role in drug design and development.^1,2

It is postulated that in living organisms these cyclic compounds have reduced metabolism in comparison to their open-chain congeners.³ Indeed, conformationally restricted amino acids have been successfully used in the peptidomimetic drug design as surrogates of proline, a natural amino acid that is found in those secondary structure elements that bring about biological action of peptides.

Many commercial drugs have been designed through the replacement of the proline with its unnatural conformationally restricted analogs. Among these launched drugs are an anticoagulant agent Ximelagatran 1⁴, recently introduced angiotensin-converting enzyme (ACE) inhibitor Zabicipril 2⁵, and a new oral hypoglycemic (anti-diabetic) drug Saxagliptin 3⁶ (Figure 1). Conformationally restricted amino acids are also involved in the synthesis of prolyl endopeptidase inhibitors, as exemplified by compound 4⁷ in Figure 1.

Several representative conformationally restricted amino acids available from Life Chemicals are depicted below. The full database of the title structures can be provided upon request at orders@lifechemicals.com.

References

1. (a) Zanuy, D.; Ballano, G.; Jimenez, A. I.; Casanovas, J.; Haspel, N.; Cativie, C.; Curco, D.; Nussinov, R.; Aleman, C. J. Chem. Inf. Model. 2009, 49, 1623-1629. (b) Komarov, I. V.; Grigorenko, A. O.; Turov, A. V.; Khilya. V. P. Russ. Chem. Rev. 2004, 73, 785–810.
2. Lasota, A.; Fraczak, O.; Lesniak, A.; Muchowska, A.; Lipkowski, A. W.; Nowakowski, M.; Ejchart, A.; Olma, A. J. Pept. Sci. 2015, 21, 120-125.
3. Komarov, I. V.; Grygorenko, O. O.; Radchenko, D. S.; Artamonov, O. S.; Kostyuk, A. N.; Tolmachev, A. N. Chemistry Today 2006, 24, 22-23.
4. Gustafsson, D.; Bylund, R.; Antonsson, T.; Nilsson, I.; Nyström, J.-E.; Eriksson, U.; Bredberg, U.; Teger-Nilsson, A.-C. Nature Reviews/Drug Discovery 2004, 3, 649-659.
5. Vincent, M.; Pascard, C.; Cesario, M.; Rémond, G.; Bouchet, J.-P.; Charton, Y.; Laubie. M. Tetrahedron Lett. 1992, 33, 7369.