Constrained Glypromate^® analogues incorporating a bicyclic proline surrogate

Neurodegenerative diseases affecting the central nervous system, such as Alzheimer’s and Parkinson’s Diseases, result from progressive degeneration and/or death of neurons, without curative treatments currently available. Glypromate^® is a neuroprotective tripeptide obtained by the N-terminal cleavage of insulin-like growth factor 1 (IGF-1), which is found in brain tissue. In vitro and in vivo studies have demonstrated that this neuropeptide is capable of stimulating the release of acetylcholine and dopamine and acting as neuroprotective. However, the clinical trials with this neuropeptide failed in phase III.

Constrained proline mimetics of Glypromate^®, such as Trofinetide^®, whereupon the alpha-proton of proline was substituted by a methyl group, is currently undergoing clinical trials for Rett and Fragile X syndrome, proving that highly constrained proline mimetics may be beneficial for the activity of this peptide. Also, a Glypromate^® analogue with pipecolic acid instead of L-proline demonstrated good stability in comparison with Glypromate^®.

In this work, the design, synthesis, and biological evaluation of Glypromate^® peptidomimetics using 2-azanorbornane as a proline surrogate is described. Following a diversity-oriented synthesis approach, four novel highly constrained Glypromate® analogues were synthesized in excellent global yields (75-84%) using a one-pot protocol in peptide synthesis.

Neuroprotective assays performed in human neuroblastoma SH-SY5Y cells using 6-hydroxydopamine (6-OHDA) as stress inducer demonstrated that Glypromate® analogues display superior neuroprotection in comparison with the parent peptide (100 mM concentration) and a remarkable percentage of recovery (29.7-40.0%) after 6-OHDA injury in contrast with 12.8% found for Glypromate^®.