Design, Synthesis, And Structure-activity-relationship Of Tetrahydrothiazolopyridine Derivatives As Potent Smoothened Antagonists

Hedgehog(Hh) signaling pathway is a very important pathway during embryonic development which controls cell multiplication and differentiation. Aberrant Hh signaling during development can lead to abnormality. In adults, Hh pathway can help repair tissue and is much less active. However, aberrant reactivation can lead to numerous human cancers, including medulloblastoma and basal cell carcinoma. The Smoothened(SMO) receptor is a key component of Hh pathway. Inhibition of SMO can blockade Hh signaling, and therefore represents a promising approach toward novel anticancer therapy.Nowadays, a lot of small molecule inhibitors of the Hh pathway have been reported. Among these inhibitors, Vismodegib(GDC-0449) was approved by the FDA to treat patients who suffer from advanced basal cell carcinoma in 2012. The success of Vismodegib indicates that inhibition of Hh pathway is feasible to treat cancers. However, poor solubility of Vismodegib and acquired drug resistance need scientists develop new scaffolds which improved physical-chemical properties and overcome acquired drug resistance.The skeleton of Vismodegib was composed by sp2-hybridized carbons, leading to poor solubility and a high melting point. We introduced sp3-hybridized carbons to design a series of new compounds that based on a tetrahydrothiazolopyridine scaffold. The new compounds demonstrated excellent inhibition of Hh signaling pathway which was comparable to or better than that of Vismodegib. Furthermore, compounds had a better solubility and a much lower melting point than Vismodegib. Compounds 11 and 30 showed good pharmacokinetic profiles with 34% and 77% oral bioavailability in rat, respectively. These results strongly support further study on pharmacodynamics.Some of these new compounds exhibit chemical instability. So we added some small molecular groups to the new scaffold to eliminate the site of potential metabolism and get more stable compounds. The synthesis of compounds and subsequent cell experiments are in progress.