Discovery of the Orally Effective Thyrotropin-Releasing HormoneMimetic: 1?{N?[(4S,5S)?(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)?L?alanyl}-(2R)?2-methylpyrrolidine Trihydrate(Rovatirelin Hydrate)

摘要

We have explored orally effective thyrotropin-releasinghormone (TRH) mimetics, showing oral bioavailability and brainpenetration by structure?activity relationship (SAR) study on the basis ofin vivo antagonistic activity on reserpine-induced hypothermia in mice. Byprimary screening of the synthesized TRH mimetics, we found a novel TRHmimetic: L-pyroglutamyl-[3-(thiazol-4-yl)-L-alanyl]-L-prolinamide with a highcentral nervous system effect compared with TRH as a lead compound.Further SAR optimization studies of this lead compound led to discovery of anovel 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 clinicaltrials.