Prolonged oral
creatine administration resulted in remarkable neuroprotection in experimental models of brain
stroke. However, because of its polar nature
creatine has poor ability to penetrate the blood-brain barrier (BBB) without specific
creatine transporter (CRT). Thus, synthesis of hydrophobic derivatives capable of crossing the BBB by alternative pathway is of great importance for the treatment of acute and chronic neurological diseases including
stroke,
traumatic brain injury and hereditary CRT deficiency. Here we describe synthesis of new hybrid compounds-creatinyl
amino acids, their neuroprotective activity in vivo and stability to degradation in different media. The title compounds were synthesized by guanidinylation of corresponding sarcosyl
peptides or direct
creatine attachment using
isobutyl chloroformate method. Addition of lipophilic counterion (
p-toluenesulfonate) ensures efficient
creatine dissolution in DMF with simultaneous protection of guanidino group towards intramolecular cyclization. It excludes the application of expensive guanidinylating
reagents, permits to simplify synthetic procedure and adapt it to large-scale production. The
biological activity of creatinyl
amino acids was tested in vivo on
ischemic stroke and NaNO(2) -induced
hypoxia models. One of the most effective compounds-creatinyl-
glycine ethyl ester increases life span of experimental animals more than two times in
hypoxia model and has neuroprotective action in brain
stroke model when applied both before and after
ischemia. These data evidenced that creatinyl
amino acids can represent promising candidates for the development of new drugs useful in
stroke treatment.