We have explored orally effective thyrotropin-releasing hormone (TRH) mimetics, showing oral bioavailability and brain penetration by structure–activity relationship (SAR) study on the basis of in vivo antagonistic activity on reserpine-induced hypothermia in mice. By primary screening of the synthesized TRH mimetics, we found a novel TRH mimetic: l-pyroglutamyl-[3-(thiazol-4-yl)-l-alanyl]-l-prolinamide with a high central nervous system effect compared with TRH as a lead compound. Further SAR optimization studies of this lead compound led to discovery of a novel orally effective TRH mimetic: 1-{N-[(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine trihydrate (rovatirelin hydrate), which was selected as a candidate for clinical trials.

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