Synthesis And Evaluation Of In Vivo Anti-Hypothermic Effect Of The N- And C-Terminus Modified Thyrotropin-Releasing Hormone Mimetic: [(4s,5s)-(5-Methyl-2-Oxooxazolidine-4-Yl)Carbonyl]-[3-(Thiazol-4-Yl)-L-A Lanyl]-L-Prolinamide

We explored orally effective thyrotropin-releasing hormone (TRH) mimetics, which show high central nervous system effects in structure-activity relationship studies based on in vivo antagonistic activity on reserpine-induced hypothermia (anti-hypothermic effect) in mice starting from TRH. This led us to the TRH mimetic: [(4S, 5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-[3-(thiazol-4-yl)-L-alanyl]-L-prolinamide 1, which shows a higher anti-hypothermic effect compared with that of TRH after oral administration. We next attempted further chemical modification of the N- and C-terminus of 1 to find more orally effective TRH mimetics. As a result, we obtained several N- and C-terminus modified TRH mimetics which showed high anti-hypothermic effects.